Y2 LCRS Pharmacology and Therapeutics

Drugs of Abuse Class 3: Stimulants

'Uppers' - Reverse the effects of fatigue on both mental and physical tasks. e.g. Nicotine - Cigarette smoke: o Volatile phase = 95% (500+ gaseous compounds incl nitrogen, carbon monoxide, benzene, ammonia o Particulates = 5% (3500+ different compounds incl the alkaloid NICOTINE) o Tar = Particulate matter without alkaloids and water content. Contains many carcinogens.

Hyperkalaemia as S/E of ACEi and ARBs

** Hyperkalaemia - ACEi, ARB - care with K+ supplements or K+-sparing diuretics. as sodium not being transported in with water, potassium not excreted out. o Aldosterone promotes K+ loss so aldosterone inhibitors (ACEi, ARBs) produce a hyperkalaemia. **o Renal failure (in patients with renal artery stenosis) - ACEi, ARBs. o Glomerular filtration is maintained by AngII so you need to be careful in renal failure patients.

What do ACEi end in?

-pril

MUSCARINIC RECEPTOR ANTAGONISTS - Unwanted effects

1) Hot as hell - decreased sweating, thermoregulation 2) Dry as a bone - decreased secretions 3) Blind as a bat - cyclopegia (paralysis of eye muscles so no accommodation). paralyse lens 4) Mad as a hatter- CNS disturbance (i.e. tremors etc.).

Nicotine half -life

2-3 hours

What is a adverse drug event?

Adverse Drug Event: preventable or unpredicted medication event---with harm to patient. often due to medication errors which are preventable. o Medication errors AND adverse drug reactions.

What is a local anaesthetic?

Drugs which reversibly block neuronal conduction when applied locally

antibiotic resistance mechanism 5 - Hyperproduction

Hyperproduction: •Bacteria significantly increase levels of DHF reductase **Example •E Coli produce additional DHF reductase enzymes making trimethoprim less effective. **not very common mechanism of resistance as bacteria has to work a lot harder to create these extra enzymes.

What are the two main components of cannabis?

THC and cannabidiol

Carbamazepine is a potent CYP450 enzyme inducer. True./ False

True

Clopidogrel antagonises the P2Y12 sub-type of ADP receptor. True/ False

True

Cocaine can cause euphoria. True/ False

True

Cocaine enhances sympathetic transmission by inhibiting uptake 1. True/ False

True

Atenolol

b1 blocker

What do nicotinic receptor antagonists do to secretions?

decreases

How would you demonstrate statistically in a larger survey that β-blockade had occurred?

do a larger and more varied cohort - more sexes, more ages, ethnicity etc. this shows it works in the cohort.

Haemostasis vs thrombosis

haemostasis is physiological blood clotting; thrombosis is pathological

Example of methylation Phase 2 metabolism

levodopa

what does elevated troponin indicate?

o elevated troponin - suggests breakdown of myocardial tissue (potentially MI?)

Describe three different types of formulations that may be used to deliver a drug via the oral route.

pill/capsules, solutions/syrups powders

Dobutamine summary

-It has very little β2 action and lacks isoprenaline's reflex tachycardia effect -It has a very short plasma half-life of two minutes, as it is rapidly metabolised by COMT **Clinical Uses: Heart block and is administered by intravenousinfusion.

What do fluconazole and amphotericin treat?

1) Azoles - Fluconazole: § Inhibit CYP450 enzymes involved in membrane Ergosterol synthesis. § Fluconazole treats - candidiasis, systemic infections. 2) Polyenes - Amphortericin: § Binds to Ergosterol and creates channel pores. § Amphortericin treats - systemic infections.

Nicotinic receptor vs muscarinic

1) Nicotinic Receptor •Found in ALL autonomic ganglia •RAPID •Receptor is ion channel linked (ionotropic - Type 1) •Acetylcholine binds à opens an ion channel à •allows sodium/calcium influx and allows transmission 2) Muscarinic Receptors •Muscarinic receptors are found in any tissue innervated by a post-ganglionic parasympathetic fibre •Muscarinic receptors are Type 2 - G-protein Coupled •These are MUCH SLOWER than nicotinic receptors NOTE: sweat glands also have muscarinic receptors (sympathetic)

Thrombosis stages (3)

1) initiation 2) amplification 3) propagation

Imporant considerations for drugs

1) what is drug target - e,g. adrenoreceptors, muscarinic and nicotinic receptors 2) where is drug target 3) what is end result of interaction?

Potentially curative therapies for IBD

1. - Manipulation of the microbiome 2. - Biologic Therapies a) Anti-TNFa eg Infliximab b)Many others

ANS system at rest

At rest: -Lungs, eyes and HR dominated by parasympathetic -Arterioles controlled by sympathetic

Pathogenesis of atherosclerotic plaques

Atherosclerosis is an inflammatory fibroproliferatve disease

Protease inhibitors are potent CYP450 enzyme inducers. True/ False

FAlse

Different types of adrenoreceptors

a1,a2, b1, b2

Alcohol acute effects CNS

§ Depressant effect mainly (like cannabis). o Degree of CNS excitability dependent upon the environment and personality of the individual. **low doses often increases socialising ability and can excite CNS; but after high doses can get depressant.

Rivaroxaban

•Rivaroxaban (oral) - factor Xa inhibitor

NT for sweat gland

Ach in both

This range of side effects would severely limit the therapeutic value of a muscarinic antagonist. How have these problems been overcome to produce a therapeutically useful drug?

Administer drug topically (e.g. inhaling) to reduce dose required and the drugs used such as Ipratropium bromide do not readily cross into the bloodstream. (lipid insoluble/charged - e.g. with a quarternary amine )

Reasons for drug variability

Both the desired and unwanted responses to any given drug may vary between individuals. The reasons for this can be subdivided into: 1. ABSOLUTE may be deliberate or accidental eg. due to: a) error in prescription or dispensing b) patient non-compliance c) drug formulation 2. RELATIVE overdose or underdose Because the patient varies from the text book standard. Some of the factors which may cause this variation include: a) Environmental exposure to chemicals, including other drugs enzyme induction enzyme inhibition b) Food intake - drugs may interact chemically with components of food; this may alter their absorption foods delay gastric emptying and alter gastric pH. c) Fluid intake most drugs are better absorbed if taken with water eg may dissolve better fluids may stimulate gastric emptying. d) Age Newborn infants have more body water than adults poorer renal function, with immature tubular secretion an immature blood brain barrier lower capacity for drug metabolism. The elderly have an overall deterioration in many physiological functions that may affect i) drug absorption: decreased absorptive surface of small intestine altered gastric and gut motility increased rate of gastric emptying ii) drug distribution: reduced lean body mass and body water, relative increase in fat lipid soluble drugs have increased Vd and decreased blood levels water soluble drugs have decreased Vd and increased blood levels reduced plasma albumin, so fewer plasma protein binding sites iii) drug metabolism splanchnic and hepatic blood flow decrease by 0.3 - 1.5%/year liver size and hepatocyte number decrease hepatic enzyme activity and induction capacity decrease iv) drug excretion - changes in renal function are probably the most important factors affecting drug handling in the elderly. With age there is a steady decline in the following factors: reduced renal mass reduced renal perfusion reduced glomerular filtration rate reduced tubular excretion These changes are normal - the situation may be compounded if the patient has renal disease. v) organ sensitivity - the elderly tend to be more sensitive to CNS active drugs e) Disease i) General nutritional status unbalanced diets may lead to deficiency states and enzyme abnormalities starvation - decreased plasma protein binding and metabolism obesity - increased lipid fraction ii) Gastrointestinal disorders e.g. achlorhydria, coeliac disease, Crohn's disease altered drug absorption iii) Congestive heart failure (especially in the elderly) may lead to reduced splanchnic blood flow intestinal mucosal oedema reduced hepatic clearance iv) Kidney failure (especially in the elderly) may lead to decreased drug excretion leading to toxicity water overload leading to changes in drug concentrations in different body fluid compartments v) Liver failure may lead to reduced metabolism reduced first pass metabolism (hence increased bioavailability) decreased biliary secretion and hence decreased removal decreased albumin synthesis and hence reduced plasma protein binding vi) Other acute or chronic disease states

Ethanol can induce cutaneous vasoconstriction. True/ False

FAlse

Which PD medication increases the amount of DA produced in nerve terminals?

Levodopa

What is the target of clopidogrel?

P2Y12 receptor

What do nicotinic receptor antagonists do to smooth muscle?

Pupil dilation; ¯ G.I. tone bladder dysfunction; bronchodilation

Protease inhibitors can be used in the treatment of HIV and hepatitis C. True/ False

TRue

Agents affecting the renin angiotensin aldosterone system

a. Angiotensin converting enzyme inhibitors b. Angiotensin (AT1) receptor antagonists c. Aldosterone antagonists d. Beta blockers

NTs of sympathetic NS (thoracolumbar)

adrenal medulla has no post ganglionic nerve; releases A (80%) and NA (20%) into bloodstream

propanolol

b1, b2 antagonist

What type of reaction converts an alcohol to an aldehyde? A.Reduction B.Methylation C.Oxidation D.Acetylation

c.Oxidation

ACE inhibitors are more effective in the treatment of hypertension than angiotensin receptor blockers. True or False?

false

Example of acetylation Phase 2 metabolism

isoniazid

How does aripiprazole differ from other antipsychotic drugs?

it is a partial agonist at D2 and 5-HT1A receptors

Which neuronal dopaminergic pathway extends from VTA to NAcc?

mesolimbic pathway (reward)

What is a cholinomimetic drug

mimic or modify the effects of acetylcholine

pilocarpine

muscarinic agonist. constricts pupil, lens thickening (near accomodation)

Carvedilol

non-selective a1 and b1 blocker

Endogenous opioid peptide examples

o Endogenous opioid peptides: a) Endorphins b) Enkephalins c) Dynorphins/neoendorphins o They act via specific 'opioid' receptors

Alcohol in doses vs in one high dose

o One high-dose alcohol bolus will saturate the enzymatic system and lead to a higher intoxication as opposed to the same absolute amount of alcohol over say 4 separate doses. *§ Liver metabolism: o Alcohol --> acetaldehyde (toxic) via: § 75% - Alcohol dehydrogenase. § 25% - Mixed function oxidase.

Phase 1 metabolism process and purpose

o oxidation/ hydrolysis/reduction reaction o oxidation/reduction reduction CREATES new functional groups o hydrolysis unmasks o oxidation --> ELECTROPHILES o reduction/hydrolysis --> NUCLEOPHILES - N.b. the functional group serves as a point of attachment for phase II reactions - - most common phase 1 metabolism is OXIDATION (often start with HYDROXYLATION though catalysed by P450 system)

Nicotine (Nicotana tabacum)

o plant-based alkaloid o § Cigarettes produce: o 95% - volatile substances - e.g. N2, CO/CO2, benzene, HCN. o 5% - particulates - e.g. alkaloids (nicotine), tar. § Nicotine diffuses out of the tar droplets in the lungs when deposited.

Opiate vs opioid

opiate is natural (morphine, codeine) vs opioid is synthetics (anything that has opiate-like activity)

How can good bioavailability be achieved for drugs that undergo extensive first-pass metabolism?

other forms of administration e.g. inhalation, sublingual

Determine whether each equation is oxidation, reduction or hydrolysis?

oxidation, hydrolysis, reduction

Plaque rupture

tissue factor comes into contact with circulation --> coagulation pathways --> thrombus

How to treat atropine poisoning

treat with anti-cholinesterase e.g. physostigmine; increases Ach to outcompete atropine. restore muscarinic receptor function

Beta blockers are useful in angina because they reduce heart rate. True/ False

true

Under what circumstances could a drug, which undergoes 100% first pass metabolism, be therapeutically useful?

when have topical agents or prodrugs in system

Drugs of Abuse Class 2: Depressants

§ 'Downers' - Drugs that produce CNS depression. e.g. Alcohol § Effects on reward pathway: Complex! Main effect - ↑ firing rate of dopaminergic VTA neurones (via ion channels, GABAA and NMDA receptors) § Depressants - also Barbiturates, benzodiazepines & Cannabis

Alcohol Effects on foetal development

§ Foetal alcohol syndrome; (mothers drink at least 4 units/day) § Abnormal facial development (+ other anatomical abnormalities) § Growth retardation § Mental retardation (Smaller degrees of ethanol-related abnormality may occur very frequently) **Cause - Inhibition of cell division/migration??

Pros of Inhalation vs intravenous anaesthetic

§ IV is used for induction. § Inhalation is used for maintenance.

How do NSAIDs work?

§ NSAIDs inhibit prostanoid synthesis by blocking COX. § Prostanoids: o Derived from arachidonic acid. o Examples - prostaglandins, TXA2, prostacyclin. o Widely distributed and NOT stored pre-formed (once made, are released) o Receptor-mediated action.

Pathophysiology of Parkinson's

§ Severe loss of dopaminergic projection cells in SNc § Lewy bodies & neurites --> Found respectively within neuronal cell bodies & axons § Consist of abnormally phosphorylated neurofilaments, ubiquitin & a-synuclein **Loss of cells in the substantia nigra leads to a marked reduction in caudate nucleus/putamen dopamine content.

Types of lipid remnants

§ The remnant lipids are the chylomicron remnants that are very good at infiltrating the endothelial wall. § Remnants include: o VLDL. o Chylomicron remnants. o IDL. § Note - remnants are MORE important than LDLs here ****The INFLAMMATORY part of atherosclerosis is NOT caused by LDL, but by lipid remnants!***

Structures of local anaesthetics

§ cocaine - ester § lidocaine - amide § There are 3 components to a LA: o Aromatic region - very lipid-soluble/hydrophobic. o Amine side-chain - hydrophilic. o Ester or Amide bond. § Cocaine - ester - Ester smokes cocaine. § Lidocaine - amide. § One LA doesn't obey the above structure law - Benzocaine: o No basic amine group so weaker potency. useful as a surface anaesthetic e.g. for severe sore throat in a lozenge.

Problems with the lipid theory of GAs

§ more lipid soluble a GA become --> more potent. Anaesthetic potency increases in direct proportion with oil/water partition coefficient (Meyer/Overton Correlation) Meyer-Overton correlation - GAs penetrate the lipid bilayer and disrupt AP propagation: a. Evidence for - anaesthetic potency increases as lipid solubility increases. b. Evidence against - at relevant concentrations, changes in the bilayer was minute and no changes in lipid bilayer proteins was seen (which would be changed if GAs disrupted AP propagation). Also did not see how the GAs could interfere with membrane proteins (e.g. channel proteins) to change bilayer permeability.

Opioids pharmacokinetics

§ route of administration: oral and IV § opioids are weak bases - mostly pKa> 8; so more readily ionised in stomach (pH lower than 8) and the blood and thus poorly absorbed. from stomach to SI to blood, pH increases --> better absorption but still not much unionised so probably around 20% can leave and access tissues. § Lipid solubility - Methadone/Fentanyl >> Heroin > Morphine (more lipid soluble, more potent).

Reverse cholesterol transport

*§ Reverse cholesterol transport - the removal of cholesterol from vessel walls back to the liver by HDL. *

A 27-year-old woman gives birth to a baby boy via caesarean section. That evening the woman is administered an intramuscular injection of morphine as an analgesic to help treat post-operative pain. Two days later, once the pain has subsided, the morphine injections are stopped and replaced with oral ibuprofen. 1) Describe how the two different analgesics would reach the intended site of action i.e. the post-caesarean scar tissue. 2) How do you think the two different routes of administration would influence the bioavailability of the respective drugs? 3) How do you think the two different routes of administration would influence the efficacy of the respective drugs? 4) After a certain period of time, equilibrium between plasma morphine/ibuprofen and tissue morphine/ibuprofen would be reached. How does drug metabolism influence this equilibrium?

1) § Morphine i.m. - injected into the skeletal muscle. The drug can then diffuse into the skeletal muscle microcirculation. The direction of flow in any tissue microcirculation is towards the venous system, therefore the morphine will enter the venous system and be returned to the heart. The heart will then eject the morphine firstly into the pulmonary circulation then back to the heart and finally into the systemic circulation at which point it can potentially access all tissues. § Oral ibuprofen - Ibuprofen would need to pass first to the stomach and then to the small intestine (where most absorption in the GIT occurs). The ibuprofen would then need to diffuse across from the small intestine to the hepatic portal veins which send blood to the liver. It is at this point that a certain degree of metabolism can occur (first pass metabolism). The ibuprofen then passes from the liver to the vena cava and is returned to the heart. As above, the heart will then eject the ibuprofen firstly into the pulmonary circulation then back to the heart and finally into the systemic circulation at which point it can potentially access all tissues. 2) Remember that intravenous administration of a drug is associated with 100% bioavailability (proportion of the administered drug that is available within the body to exert its pharmacological effect). Intramuscular injections tend to be associated with a relatively high bioavailability - particularly since blood flow through skeletal muscle is high. The drug will diffuse into the bloodstream and a large proportion will reach the systemic circulation. Oral administration of a drug tends to be associated with a lower bioavailability since transit of the drug from the gut to bloodstream is usually less than transit of drug from muscle to bloodstream. In addition, once the drug has entered the portal vein it then has to pass through the liver, at which point drug metabolism will further reduce drug bioavailability. 3) You need to ensure you understand the difference between efficacy and effectiveness. Let us consider giving exactly the same dose of morphine via the intramuscular route and the oral route. Let us assume, as described above, that the bioavailability is greater via the intramuscular route. Everything in pharmacology is dose related - therefore if more morphine is getting to the scar tissue when administered via the intramuscular route, then the effectiveness of the drug induced analgesia is increased. However, efficacy refers to the capability of one molecule of morphine to activate one morphine (opioid) receptor. Intramuscular injection might lead to greater bioavailability and therefore a greater number of opioid-receptor complexes to be formed, but the effectiveness of each individual opioid-receptor complex (efficacy) does not change. 4) Firstly, imagine two body compartments i.e. plasma and tissue (could be any tissue). Now think in terms of simple diffusion in relation to concentration gradients. When drugs initially enter the bloodstream, the plasma concentration is obviously high. As blood passes through the various tissues, the drug diffuses from the plasma (high concentration) to the tissue (low concentration). [Caveat - the better perfused the tissue, the faster this happens] At some point an equilibrium would be reached, and there would be no net transfer from plasma to tissue and vice versa. However, drug metabolism acts to constantly shift this equilibrium. As the drug is metabolised, the plasma drug (morphine/ibuprofen) concentration reduces, and the concentration gradient shifts so that drug diffuses from tissue to plasma. Over time, as the plasma drug concentration reaches zero, the drug will be completely lost from the tissues as it diffuses back across into the plasma.

What is a drug?

A chemical substance that interacts with a biological system to produce a physiological effect.

Why are the effects of ACh transient?

It is rapidly metabolised and thus inactivated by acetylcholinesterase in the synaptic cleft.

Which one of the following effects can be attributed to anti-cholinesterase poisoning? Bronchodilation/ Reduced gut motility/ Reduced secretions/ Tachycardia/ Miosis.

Miosis.

Moclobemide

Moclobemide - reversible, selective MAO-A inhibitor (RIMA - Reversible inhibitor of MOA-A) --> reduced drug interactions (reduced cheese reaction) and reduced DoA (duration of action - need to be taken 2-3 times a day, due to reversible inhibition). *may be less effective due to not inhibiting both MAOs.

Presentation and investigations for Pulmonary Embolism

O Subsequent Presentation: •Chest pain •Dyspnoea & Tachypnoea. O Investigations: •BP = 98/63, Pulse = 108 bpm, RR = 20 bpm, SpO2 = 92% •Two-level Wells score = 6 •Multiple-detector computed tomographic pulmonary angiography (CTPA)

alpha motor neurons

The fibers that carry action potentials to cause skeletal muscle. innervate extrafusal muscle fibers.

What are the different types of drug target sites?

a) Receptors b) Ion channels c) Transport systems d) Enzymes ALL ARE PROTEINS

Tropicamide and pilocarpine both act upon the PNS side of the ANS. How does the SNS influence the ocular function (three targets)?

a. The SNS acts to increase the light entering the eye (dilation). b. Ciliary muscles, radial muscles and sphincter pupillae.

Example of aspirin phase 2 metabolism

aspirin --> hydroxylation (phase 1)--> glucuronidation (phase 2)

What does hardy-weinburg allow you to do?

derive genotypic allelic frequencies from phenotypic frequencies

Full agonist

generates maximal resposne of tissue

half-life and onset of cocaine

o Half life -<90mins o onset - seconds

Mechanisms regulating myocardial oxygen supply and demand

o Myocyte contraction = primary determinant of myocardial oxygen demand: a) ↑ H.R. = more contractions b) ↑ afterload or contractility = greater force of contraction (afterload is what resistance in systemic vessels that heart tries to overcome to pump blood) c) ↑ preload = small ↑ in force of contraction ( 100% ↑ ventricular volume would only ↑ F.O.C. by 25%). More preload returning to heart, means needs to pump more blood out (more SV). *Myocardial oxygen supply: a) Coronary blood flow b) Arterial O2 content

PGE2 pyrogenic action

o PGE2 stimulates hypothalamic neurones initiating a rise in body temperature --> hyper-pyrexia. o NSAIDs have been shown to reduce a raised temperature in influenza.

Comparison of side effects from treatment of CD with Prednisolone versus Budesonide

o Prednisolone S/E greater than Budesonide (topical)

How do opioids work?

o They act via specific 'opioid' receptors and mimicking the actions of endogenous opioid peptides. o Endogenous opioid peptides: a) Endorphins b) Enkephalins c) Dynorphins/neoendorphins

Examples of 4 opiates

o morphine o codeine o thebaine o papaverine

Drug target for increasing stomach contractility

o muscarinic sub type 3 or nicotinic o gastric smooth muscle (increase contraction) , endocrine cell (increased gastrin), parietal cell (increased acid production)

Wells Score

test used to assess an individual's risk for DVT. o 9 point criteria scored out of 10 points. o so 5 is quite high

Commoun causes for ADRs

§ Antineoplastics - cytotoxic drugs. § Cardiovascular drugs. § NSAIDs/analgesics. § CNS drugs. (these top 4 account for 2/3rds of fatal ADRs) § Antibiotics. § Anticoagulants. § Hypoglycaemics. § Antihypertensives. **Note that ADR frequency increases with increased individual drug use.

HDL cholesterol

§ HDL - protective effect for atherosclerosis & CHD events. o HDL tends to be low when TG are high. o HDL is lowered by - smoking, obesity, physical inactivity.

Drug Therapies for cholesterol (Effect of Lipid-Modifying Therapies on Lipids)

§ Historical order. § Bile acid Sequestrants - poor compliance (make feel ill, bloated) § Nicotinic acid - increase HDL well but SEs. § Statins - first line treatment for dyslipidaemia and are highly effective at lowering LDL. Also, have good compliance

Opioids - nausea and vomiting

§ Low-dose opioids active Mu receptors in the CTZ (Chemoreceptor Trigger Zone) and stimulate vomiting. o The Mu receptor stimulates disinhibition by switching OFF GABA secretion --> activate CTZ --> medullary vomiting centre

Which route in drugs of abuse is the fastest for onset of euporia?

§ inhalational o route (ascending order for onset of euphoria): oral < intranasal < IV < inhalational. o classification: narcotic, 'upper', 'downer', miscellaneous

Prevalence and incidence of epilepsy

•Prevalence between 2-7% of the population •Incidence increased over the last 30-40 years

Pathophysiology of hypertension

*BP = TPR x CO § Hypertension facts: o Hypertension = >140/90mmHg (normal + 20/10). o The MOST important risk factor for stroke (50%); major risk factor MI and CKD. o Accounts for ~25% of HF cases (70% in elderly). o Ultimate goal of hypertension therapy --> reduce mortality from cardiovascular or renal events

Give three reasons why excipients are added to a drug

- formulation.flavourings/colourings - stabilisers - bulking materials to make drug handleable

ADR Detection (2 ways)

1) Subjective report: -patient complaint- yellow-card system. 2) Objective report: a) direct observation of event b) abnormal findings: •physical examination •laboratory test •diagnostic procedure *Rare events will probably NOT be detected before a drug is marketed.

Summary of therapies for IBD

1) Supportive therapies (for the acutely sick patient): o Fluid/electrolyte replacement. o Blood transfusion or oral iron. o Nutritional support - as malnutrition is common. 2) Classic symptomatic treatments - we can't cure these diseases outright. either for active disease or prevention or remission: o Glucocorticoids - e.g. prednisolone. o Aminosalicylates - e.g. mesalazine. o Immunosuppressives - e.g. azathioprine. 3) Curative (potentially) treatments: o Manipulation of the microbiome. o Drugs (biologic therapies): § Anti-TNF-a (e.g. infliximab). § Anti-a-4-integrins (e.g. natalizumab).

Bacterial wall inhibitors

1.PtG synthesis: •Glycopeptides (e.g. Vancomycin) bind to the pentapeptide preventing PtG synthesis. 2.PtG transportation •Bacitracin inhibits bactoprenol regeneration preventing PtG transportation. 3.PtG incorporation •b-lactams bind covalently to transpeptidase inhibiting PtG incorporation into cell wall •b-lactams include: a) Carbapenems b) Cephalosporins c) Penicillins 4.Cell wall stability •Lipopeptide - (e.g. daptomycin) disrupt Gram +ve cell membrane •Polymyxins - binds to LPS & disrupts Gram -ve cell membranes

Glutamatergic Synapse Neurotransmission

1.Voltage-gated Na+ channel (VGSC) opens --> membrane depolarisation 2.Voltage-gated K+ channel (VGKC) opens --> membrane repolarisation 3.Ca2+ influx through voltage-gated calcium channels (VGCCs) --> vesicle exocytosis a)Synaptic vesicle associated (SV2A) protein allows vesicle attachment to presynaptic membrane 4.Glutamate activates excitatory post-synaptic receptors (e.g. NMDA, AMPA & kainate receptors) **often overactive in epilepsy.

Which of the following effects would be observed with a non-depolarising neuromuscular block? A.Initial muscle fasciculations B.Irreversible nAChR blockade C.A flaccid paralysis D.Increased arterial pressure

A. flaccid paralysis

NT used in the somatic NS

ACh

antibiotic resistance mechanism 2 - Additional target

Additional target: •Bacteria produce another target that is unaffected by the drug. **Example •E Coli (gram-ve) produce different DHF reductase enzyme making them resistant to trimethoprim.

Aspirin and morphine equilibrium when accept/donate protons

Aspirin - weak acid (proton donor); morphine is weak base (proton acceptor).

Anticholinesterase drugs can be used to treat which of the following conditions? A.Asthma B.Glaucoma C.Hypotension D.Motion Sickness

B.Glaucoma

What route is nicotine administration fastest? A.Oral B.Inhalation C.Intranasally D.IV

B.Inhalation

What occurs in phase 2 metabolism?

Conjugation i.e. glucuronidation, sulphation, acetylation, glutathione, methylation, amino acid conjugation etc. addition of water soluble group

HIV integrase inhibitors

DNA integration •Viral integrase inserts viral DNA into host DNA **Integrase inhibitors: •Raltegravir - first of 3 licensed integrase inhibitors

Inflammation in Atherosclerosis

Damage to cells lining the blood vessels elicits inflammatory response. Immune system sends in macrophages LDL cholesterol becomes trapped and engulfed by macrophages. Macrophages swell (foam cells); eventually become cells of plaque.

Side effects of ACEi and ARBs

Drugs - ARBs and ACEi: e.g. Enalapril, Losartan. Generally well tolerated, especially ARBs. *Side effects: a) Cough - ACEi: due to bradykinin (as not broken down anymore) - exacerbates cough b) Hyperkalaemia - ACEi, ARB - care with K+ supplements or K+-sparing diuretics. as sodium not being transported in with water, potassium not excreted out. o Aldosterone promotes K+ loss so aldosterone inhibitors (ACEi, ARBs) produce a hyperkalaemia. c) Renal failure (in patients with renal artery stenosis) - ACEi, ARBs. o Glomerular filtration is maintained by AngII so you need to be careful in renal failure patients. d) Hypotension - ACEi, ARBs (can get dizziness) e) Urticaria/angioedema - ACEi rarely. f) Foetal injury - ACEi, ARBs.

•Tolerance to the euphoric effects of drugs of abuse (e.g. heroin & cocaine) can occur after repeated use. Which form of tolerance would not involve any change in the cells that mediate the euphoric effects? A: Receptor desensitisation B: Receptor down-regulation C: Exhaustion of mediator stores D: Receptor up-regulation E: Increased metabolic degradation

E: Increased metabolic degradation

Psychological effects of cannabis

Effects on perception; colours seem brighter, music more vivid, emotions more poignant. Perceived time goes faster than clock time.

Cocaine effect on reward pathway

Effects on reward pathway: Inhibit reuptake of dopamine in the NAcc.

VGCC blockers in epilepsy treatment

Ethosuximide: a) Pharmacodynamics: § T-type Ca2+ channel antagonist --> reduces activity in relay thalamic neurones. Prevents excitation of glutamatergic neurones. T-type Calcium channel found more in CNS and cardiac pacemaker cells. L-type found in cardiac myocytes and VSMCs. b) Pharmacokinetics: § Long half-life (50 hours). Reasonably fast onset too. c) Indications: § Absence seizures

Anaphylaxis is a local allergic reaction. True or False?

False

Anaphylaxis is usually treated with an injection of noradrenaline. True or False?

False

Aspirin increases the activity of heparin. True or False?

False

Aspirin induces thromboxane A2 synthesis. True or False?

False

Aspirin reversibly inhibits cyclo-oxygenase enzymes. True or False?

False

Atypical neuroleptic drugs are commonly associated with extrapyramidal side-effects. True/ False

False

Beta blockers are useful in angina because they cause up-regulation of alpha adrenoceptors. True/ False

False

Beta blockers are useful in angina because they cause vasoconstriction. True/ False

False

Treatment options for glaucoma

Glacoma: •Increased intraocular pressure •Usually caused by poor drainage of the aqueous humour. •Aqueous humour is produced by the blood vessels in the ciliary body via the actions of carbonic anhydrase **TREATMENT - examples: a) β1-antagonists (reduce aqueous humour production) b) Alpha agonists c) Cholinomimetics d) prostaglandin analogues e) carbonic anhydrase inhibitors

Which of these drugs would be least effective for E. Coli? Quinolones, Macrolides, Sulfonamides, Rifamycins, Glycopeptides?

Glycopeptides - as affect cell wall in gram positive bacteria. Others affect intracellular structures. E. Coli is gram negative

Gemma suffers from mild asthma. One of her friends who is a medical student told her that histamine can exacerbate asthma, so she purchased a course of over the counter antihistamine tablets in the hope that it would prevent her asthma symptoms. However, it didn't work. Why not?

Histamine is only one of many bronchoconstrictors in the airways - the percentage contribution of histamine to the overall bronchoconstriction is too small for its blockade to give a clinically useful bronchodilator effect. o other bronchoconstrictor mediators: bradykinin, prostaglandins (D2/F2 alpha), leukotrienes (C4,D4, E4), ATII, endothelin, platelet activating factor. ** only steroids can downregulate all of these things

Mr E - results: 6 months ago; BP 200/110, Cholesterol 5.3mmol/l, HIV+ viral load 350 copies/ml (low) Currently; BP 190/105, Cholesterol 6.8mmol/l, HIV+ viral load 10 copies/ml (undetectable). How would you interpret the results above? What action would you consider?

Hypertensive. BP has reduced slightly, cholesterol is high (normal level is 5mmol/l) and has increased, HIV viral load is significantly reduced.Maybe change combo of hypertensives? Statins and lifestyle as well.

GAs - Mechanism of action: Neuroanatomy -•Suppression of reflex responses

In the dorsal horn of spinal cord, GABAAR are at a high density: o Depression of reflex pathways in spinal cord.

Pharmacokinetics why is it important

Is important as determines the 'dose' of drug available to tissues

What effect will injected adrenaline have on sympathetic nerves?

It is important at this early stage that you appreciate that an 'agonist' interacts with its corresponding receptor. The point I want to stress is that adrenaline will produce its effect by binding to adrenoceptors within specific effector tissues (e.g. the lung, the heart etc). It will not induce its effects via an increase in sympathetic activity. **NB - Just for completeness I have to state that there are some adrenergic receptors on sympathetic nerves, so adrenaline can have some effect on sympathetic activity. However, you will only be tested on the effects of adrenaline on adrenergic receptors in effector tissues.

What is the gold-standard medication for Parkinson's disease? Levodopa/ Carbidopa/ Pergolide/ Selegiline/ Entacapone

Levodopa

Dopaminergic pathways

Major locations: 1) Nigrostriatal pathway - susbstantia nigra pars compacta (SNc) to the striatum (putamen and caudate nucleus). Inhibition results in movement disorders e.g. Parkinsons. 2)Mesolimbic pathway - ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc). Brain reward pathway. (implicated in schizophrenia) 3)Mesocortical pathway - VTA to the cerebrum. Important in executive functions & complex behavioural patterns (implicated in schizophrenia) 4)Tuberoinfundibular pathway - arcuate nucleus of the hypothalamus to the median eminence & pituitary gland. Inhibition results in hyperprolactinaemia. o Regulate hormone secretion.

A 75-year-old man is diagnosed with glaucoma and is treated with a α1 selective adrenoceptor agonist. The therapeutic effects of the drug are partly due to which of the following functions? Dilation of the pupil/ Activation of carbonic anhydrase/ Accommodation for near vision/ Opening of scleral spur/ Ocular vasoconstriction.

Ocular vasoconstriction

What is general anaesthesia?

Only one defining feature for all general anaesthetics; 'Induce a loss of consciousness at low concentrations' and 'induce an increasing lack of responsiveness at higher concentrations'. Clinically desirable: 1.Loss of consciousness at low concn 2.Suppression of reflex responses at high concn 3.Relief of pain (analgesia) 4.Muscle relaxation 5.Amnesia **the greyed effects are generally covered by different drugs. o Loss of consciousness - at LOW concentrations. o Suppression of reflexes - at HIGH concentrations.

Where in kidney are some lipid-soluble kidneys reabsorbed?

PCTs and DCTs

§ A 52-year-old woman has been successfully treated for hypertension for a number of years with losartan (angiotensin II receptor blocker). In the last 6 months, this lady's hypertension has gradually worsened. As a result, her GP suggests switching to another angiotensin II receptor blocker, candesartan. § Explain why an angiotensin II blocker is utilised to treat hypertension.

The ARBs' mechanism of action, selective inhibition of angiotensin II by antagonism of the angiotensin II receptors produce their blood pressure lowering effects by antagonizing angiotensin II-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic response.

prazosin

alpha 1 antagonist

Opiate receptors - depressor or excitator?

depressant at cellular level

Phentolamine (alpha antagonist side effects)

diarrhoea - overactive GIT and GI motility

Serum cholesterol and mortality in USA

in some places e.g. mediterranean, the cholesterol is mediated by other factors e.g. mediterranean diet.

Pharmacokinetics of MAOIs

o Rapid oral absorption o Short plasma t1/2 (few hrs) but longer d.o.a. due to inrreversible binding to MAO o Metabolised in liver; excreted in urine § Unwanted effects: o Atropine-like effects (anti-PNS effects) - but less so than TCAs. o Postural hypotension - common. o Sedation - causes seizures in OD. o Weight gain - possibly excessive. o Hepatotoxicity - hydrazines, rare.

Polygenic control

o Several genes act together to give rise to a CONTINUOUS or UNIMODAL (GAUSSIAN) distribution of the measured variable. It is not possible to recognise or discern the influences of single genes. o Although it is not possible to divide the population into groups of individuals with identifiably different characteristics, remember that individuals remain at the same position within the distribution and that there may be large quantitative differences between the extremes of this distribution. *Example in Drug Metabolism: Ø Salicylate conjugation with glycine or glucuronic acid

Unwanted actions of PGE2?

o Unwanted actions: § Increased pain perception (lower pain threshold) § Thermoregulation. § Acute inflammatory response. § Other - immune responses, tumorigenesis, inhibition of apoptosis (so more likely necrosis)

Antagonist

reduces activity (atropine; hexamethonium)

The clinical use of neuromuscular blocking drugs will most likely involve interference with which of following physiological processes? A: Kidney function B: Consciousness C: Body temperature regulation D: Pain sensation E: Respiration

respiration

Why would you want a drug to be water-soluble

retained in blood and delivered to excretion sites

Ritonavir is known to induce mild nausea in some patients. What would be your first course of action to try to reduce ritonavir induced nausea in patients?

take ritonavir with meals

Phase 2; Methylation

§ A methyl group is added to the electron rich atom. § S-adenosyl methionine is the conjugating agent.

Using simple diagrams, explain how levodopa helps in the treatment of Parkinsons and why it is regularly combined with carbidopa. 'sinemet' - a combination of levodopa and carbidopa.

§ Levodopa is a precursor for dopamine and is converted into dopamine by the dopa decarboxylase (DD) enzyme. Hence replying the dopamine lost due to degeneration of the nigrostriatal pathway. § Dopamine converted in the periphery by the DD enzyme, will not cross the blood brain barrier (BBB) and will cause nausea & vomiting (by activating dopamine receptors in the chemoreceptor trigger zone). § Carbidopa is a DD inhibitor, which does not cross the BBB. Therefore, preventing peripheral conversion of levodopa into dopamine and only allowing it to be converted in the central nervous system.

Pharmacokinetic properties of lidocaine and cocaine

§ Lidocaine (amide) - T1/2 = 2h. o Good absorption. stable. o 70% PPB. o Hepatic metabolism - N-dealkylation. § Cocaine (ester) - T1/2 = 1h. o Good absorption. o 90% PPB. o Hepatic and plasma metabolism - non-specific esterases. **Bupivacaine (doa ~6hr; epidural anaesthesia).

Onset of ADRs

§ Onset: o Acute <1 hour. e.g. anaphylaxis o Sub-acute 1-24 hours. o Latent >2 days.

Selected anti-arrythmics: Verapamil

§ Uses - reduces ventricular responsiveness to atrial arrhythmias. § MoA - blocks VGCC and thus depresses SA firing and subsequent AV node conduction. give more time for depolarisation. o Class IV anti-arrhythmic drug

Severity of ADRs

§Severity of reaction: a) Mild: requires no change in therapy b) Moderate: requires change in therapy, additional treatment, hospitalisation c) Severe: disabling or life-threatening ØResults in death ØLife-threatening ØRequires or prolongs hospitalisation ØCauses disability ØCauses congenital anomalies ØRequires intervention to prevent permanent injury

Aminosalicylates and UC

Ø Effective at induction and maintenance of remission also low side effects and is safe. Ø Combined oral and rectal administration probably more effective than either alone for generalised disease Ø Rectal delivery better for localised disease (proctitis) Ø Probably better than glucorticoids

Aminosalicylates and CD

Ø Ineffective in inducing remission of CD Ø A very modest amount of evidence for effectiveness in maintenance Ø However, other therapies preferable for maintenance.

Downside of anti-TNFa

ØEmerging evidence that up to 50% responders lose response within 3 years time due to production of anti-drug antibodies and increased drug clearance. ØAttempts being made to optimise dosing regimens (perhaps by giving in combo e.g. with azathioprine). **Serious effects, hence should not be used as first line treatment: Ø4x - 5x increase in incidence of tuberculosis ØAlso risk of reactivating dormant TB ØIncreased risk of septicaemia ØWorsening of heart failure ØIncreased risk of demyelinating disease ØIncreased risk of malignancy ØCan be immunogenic - azothiaprine reduces risk, but raises TB /maligancy risk **Infliximab: ØEarly use better than last resort ØCombined infliximab and azathioprine therapy recommended rather than monotherapy

Dabigatran

•Dabigatran (oral) - factor IIa inhibitor

Cardiovascular effects of COX-2 inhibitors

•Evidence that selective COX-2 inhibitors pose higher risk of cardiovascular disease than conventional NSAIDS even though mechanism is unclear o one possible route is with platelets and atherogenesis. o Mechanisms - raise BP, endothelial dysfunction, oxidative injury, etc.

NSAIDs cardiovascular effects

•NSAIDS can have serious unwanted cardiovascular effects: a) Vasoconstriction b) Salt and water retention c) Reduced effect of antihypertensives •50% deaths from NSAIDs are cardiovascular: a) Hypertension b) Myocardial infarction c) Stroke •Evidence that selective COX-2 inhibitors pose higher risk of cardiovascular disease than conventional NSAIDS even though mechanism is unclear

Examples of nicotinic receptor antagonists

•Nicotinic receptor antagonists (ganglion blocking drugs) -Hexamethonium (1st Hypotensive) -Trimetaphan (Hypotension during surgery, short acting) -Alpha-bungarotoxin - irreversibly binds to both somatic and autonomic nicotinic receptors • Muscarinic receptor antagonists -Atropine (given for organophosphate poisoning) -Hyoscine -Tropicamide •Botulinum toxin - targets snare complex, preventing exocytosis of ACh

CYP 450 Inducers examples

•The "usual suspects" -Rifampicin -Carbamazepine -(Phenobarbitone) -(Phenytoin) St John's wort (hypericin) **Induction takes hours/days

Use of NSAIDs in england

•Widely prescribed (16 million prescriptions annually in England) •6% patients reported possible adverse drug reaction •(> 15% elderly at any one time) •Available over the counter •Increased risk of GI and CVS deaths

Give three examples of beta-lactam classes

•b-lactams include: a) Carbapenems b) Cephalosporins c) Penicillins

GA MoA theory 2: molecular targets

** Molecular targets - either/and/or: 1) ALTERED SYNAPTIC FUNCTION: a) IV agents: § Enhance the GABAAR and enhance GABA transmission - subunits targeted: i) b3 - suppression of reflex responses - expressed in spinal cord. ii) a5 - amnesia - expressed in hippocampus/amygdala. b) Inhalational agents - not as powerful/selective as IV agents (hits more targets but less): i) Halogen inhalational agents: Target the GABAA (brain) /Glycine receptors (spinal cord): a1 - suppression of reflex responses (esp. in glycine); AND ALSO Decrease firing rate of neuronal NAChR (analgesic). ii) Nitrous oxide (non-halogen agents): Block NMDA-type glutamate receptors - compete with co-agonist glycine. Assumed to mediate the anaesthetic induced effects on consciousness and mobility. 2) REDUCED NEURONAL EXCITABILITY: Are INHALATIONAL agents - not as powerful/selective as IV agents (hits more targets but less). § Halogen inhalational agents: Enhance background leak of K-channels to cause hyperpolarisation of cells. i. TREK (background leak) of K+-channels --> increasing potassium efflux and hyperpolarisation. *causes the loss of consciousness

Inflammation hypothesis for AD (3/3)

** Physiology - Microglia § Specialised CNS immune cells - similar to macrophages. Protects CNS and carries out phagocytosis. §Inappropriate activation of inflammatory pathways in the brain is known to be involved in the pathogenesis of AD but there is no consensus about exactly how the inflammatory pathways contribute to neurodegeneration. § Microglia are specialised CNS immune cells and astrocytes are also facultative macrophages. There is evidence that these cells become activated in AD resulting in effects below. **Pathophysiology - Microglia: a) increased release of inflammatory mediators & cytotoxic proteins b) increased phagocytosis c) decreased levels of neuroprotective proteins. **could be due to increased tau protein. This theory is retrospectively, people who've taken long-term NSAIDs (e.g. ibuprofen) seems to be protective against AD. But if give ibuprofen after have AD, not v effective.

Unwanted effects of SSRIs

** Unwanted effects: § Fewer side effects than TCAs/MAOIs. Currently the most prescribed antidepressant. o Nausea, diarrhoea, insomnia, loss of libido. o Interacts with MAOIs - avoid co-administration. o Increases suicidality in the <18s.

antibiotic resistance mechanism 4 - Alterations in drug permeation

**Alterations in drug permeation: Reductions in aquaporins (so less AB enters bacteria) & increased efflux systems. **Examples •Primarily of importance in gram -ve bacteria

Gastric acid regulation

**Gastric acid regulation: 1.Acetylcholine (ACh) released from neurones (vagus / enteric) acts on muscarinic (M3) receptors - = increases [Ca2+]i --> increased expression of proton pumps. 2.Prostaglandins (PGs) released from local cells act on EP3 receptors - ↓ cAMP --> decreases proton pump expression and acid secretion (so are protective); hence as NSAID block prostaglandins, it increases likelihood of gastric ulcer formation. 3.Histamine released from enterochromaffin-like cells (ECL) act on H2 receptors - increases cAMP --> increases proton pump expression and acid secretion 4.Gastrin released from G-cells, acts on cholecystokinin B receptors (CCKB-R) - increases [Ca2+]i --> increases proton pump expression and acid secretion. gastrin is combatted by somatostatin which is also released by G cells. **Gastric acid secretion: • [Ca2+]i & cAMP ® translocation of secretory vesicles to parietal cell apical surface ® ↑ H+ secretion •Somatostatin - peptide that inhibits G-cells, ECL cells and parietal cells

H. Pylori effects

**Helicobacter Pylori •Gram negative, motile (means can get additional peptic ulcers), microaerophilic bacterium ( •Resides in human GI tract - exclusively colonising gastric-type epithelium **Ulcer formation: •Increased gastric acid formation - increased gastrin or decreased somatostatin results from H pylori. •Gastric metaplasia - cell transformation due to excessive acid exposure •Downregulation of defence factors - decreased epidermal growth factor & decreased bicarbonate production **Virulence: o H pylori produces Urease enzyme - catalyses urea into ammonium chloride & monochloramine --> damage epithelial cells o Urease is also antigenic --> evokes immune response which can cause damage. o Certain virulent strains produce exotoxins CagA (antigenic - induces immune response) or VacA (cytotoxic - damages cells directly) --> more intense tissue inflammation.

Effects of Azathioprine on immune responses (IBD treatment)

**It impairs: Øcell- and antibody-mediated immune responses Ølymphocyte proliferation Ømononuclear cell infiltration Øsynthesis of antibodies **It enhances ØT cell apoptosis

Gender differences in ethanol metabolism

**Women: o Body water: 50% Men: o Body water: 59% **Men have more ADH, more body water. § Men have a greater volume of body water (and women have more adipose tissue) which allows alcohol to be more widely distributed in men so at a lower concentration (more diluted). § Men have more ADH as well so more ability to metabolise o women also have 50% less Alcohol Dehydrogenase than males in the GIT.

Genetic risk factors for IBD

**genetic risk factors: o Causes incompletely understood o CD more extensively studied than UC oGenetic predisposition: •201 loci identified •People of White European origin most susceptible **combo of different cell types and mechanisms

Opioids - GIT distrubance

*In action: o Sensory neurone connected to mucosal chemoreceptors and stretch receptors detect chemical substances in the gut lumen or tension in the gut wall caused by food. o Information relayed to submucosal and myenteric plexus via interneurons. o Motor neurones release acetylcholine or substance P to contract smooth muscle or vasoactive intestinal peptide or nitric oxide to relax smooth muscle. § Many opioid receptors (kappa and Mu) are found in the myenteric plexus. o Motor neurones release Ach or substance P to contract SM. o Motor neurones release VIP (vasoactive intestinal peptide) or NO to relax SM. § Opioids cause: o Decrease in gastric emptying --> Decreased GI motility. o Increase in water reabsorption. **CONSTIPATION.

Tau hypothesis for AD (2/3)

*Physiology: § Soluble protein present in axons § Important for assembly & stability of microtubules. Helps maintain neuronal cell stability. *Pathophysiology: § Hyperphosphorylated tau is INsoluble --> self-aggregates to form neurofibrillary tangles (primarily found intracellularly) § These are NEUROTOXIC. § additionally, this also results in microtubule instability --> loss of stability of neuronal axons --> neurodegeneration. **Thought that tau aggregation occurs, then beta amyloid aggregation. So both can occur together.

Drug target site type 4: enzymes

- Catalytic proteins - rate of reactions - Drug interactions:- i) enzyme inhibitors e.g. anticholinesterases (neostigmine)- increases Ach in synapses - used to reduce IOP ii) false substrates e.g. methyldopa (instead of dopa - so methylNA formed instead and hence less effect on post-synaptic receptors and get reduced BP) iii) prodrugs e.g. chloral hydrate --> trichloroethanol in liver; is a hypnotic drug N.B. Unwanted effects e.g. paracetamol --> ALF. as the system becomes saturated and so switches to a new enzyme to break down the drug and thus creates toxic by-products. N.B. Some drugs bind very strongly to plasma proteins and so can provide a dangerous and untapped reservoir of the drug (e.g. warfarin).

Clonidine Summary

-Clonidine is a drug that is selective for α2-adrenoceptors, which are uniquely located presynaptically and act as auto-inhibitory receptors to reduce the amount of noradrenaline released into the synaptic cleft -Clonidine also has a central action on the brainstem -Within the brainstem it works on the baroreceptors in this pathway and reduces the sympathetic drive coming out of the brain Clinical uses -Treatment of hypertension and migraine as this reduces the amount of noradrenaline released in synapses, which in turn reduces sympathetic tone (reduced vascular toneà decreased TPR à Decreases BP). *-Clonidine was very good at reducing blood pressure but the patients tended to get persistent colds and generally feeling a little bit under the weather so this drug fell out of favour with patients and was dropped

Phenylephrine summary

-Phenylephrine has a selective action on α1-adrenoceptors with relatively little action on the others -It is chemically related to adrenaline but is more resistant to COMT degeneration Clinical Uses 1) VASOCONTRICTION: given intravenously or topically and therefore is used in sepsis or to counteract the hypotensive effects of local anaesthesia 2) MYDRIATIC: (in eye drops) to dilate the pupils. This is useful for inspecting the eye prior to minor procedures - the radial muscles all have α1-adrenoceptors that cause pupil dilation via contraction of these muscles when stimulated 3) NASAL DECONGESTANTS; not to treat the cold or flu virus, but its vasoconstrictor actions decrease mucus production and reduce swelling

Beta Blockers

-Their mechanism of action includes: 1) CNS to reduce sympathetic tone 2) Heart to reduce heart rate and cardiac output à Decreased BP 3) Kidneys to reduce renin production (principal effect) à Decreased AngII **A common feature in their anti-hypertensive action is a reduction in peripheral resistance

·MOST sympathetic post-ganglionic neurones release NORADRENALINE TWO exceptions

1) A preganglionic sympathetic neurone drives the release of Adrenaline (80%) and Noradrenaline (20%) from the ADRENAL MEDULLA. 2) Sweat gland (post-ganglionic neurone) - releases ACETYLCHOLINE

BDZs uses depending if long-acting or short-acting

1) ANXIOLYTICS: ('LONG-ACTING'): § DIAZEPAM (VALIUM) § CHLORDIAZEPOXIDE (LIBRIUM) § NITRAZEPAM *N.B. OXAZEPAM - t1/2 is 8 hours - use if HEPATIC IMPAIRMENT. 2) SEDATIVE / HYPNOTICS: ('SHORT-ACTING'): § TEMAZEPAM § OXAZEPAM *N.B. - NITRAZEPAM t1/2 is 28h - gives DAYTIME ANXIOLYTIC EFFECT

antibiotic resistance mechanism 1 - Destruction Enzymes

1) Production of destruction enzymes: •b-lactamases are present within bacteria and they hydrolyse C-N bond of the b-lactam ring in the antibiotic. Examples: a) Penicillins G & V combat Gram +ve bacteria. b) Flucloxacillin & Temocillin --> b-lactamase resistant. Thought to be due to steric hindrance so lactamase can't access lactam ring. Temocillin effective against gram -ve bacteria; Flucloxacillin is not. c) Amoxicillin --> Broad spectrum AB (affects gram +ve and gram -ve bacteria). that combats Gram -ve activity and is resistant to b-lactamases only when co-administered with Clavulanic acid.

Types of drug antagonism

1) Receptor blockade 2) Physiological antagonism 3) Chemical antagonism 4) Pharmacokinetic antagonism

Examples of other antidepressant drugs apart from TCA, MAOIs and SSRIs

1) Venlafaxine - dose-dependent re-uptake inhibitor - 5-HT>NA>DA. (at low dose inhibits 5-HT only, as increase dose it inhibits NA uptake too, then increased dose inhibits DA uptake too. o 2nd line for severe depression. SNRI. 2) Mertazapine - a2 receptor antagonist - inhibits negative inhibition of NA release. o Increases NA and 5-HT release. o Other R interactions (sedative) o Useful in SSRI intolerant patients.

Thrombolytics: mechanisms

1. Anticoagulants & anti-platelets - DO NOT remove pre-formed clots. prevent subsequent increases in size of thrombosis (not good for emergencies e.g. STEMI or stroke) 2.Thrombolytics •Convert plasminogen --> plasmin •Plasmin - protease degrades fibrin •Alteplase (IV) - recombinant tissue type plasminogen activator (rt-PA) **N.b. - too much plasmin can cause excessive bleeding to death. hence be caution and use in emergencies only.

What effect would blockade of nicotinic acetylcholine receptors have on heart rate; 1.At rest 2.During exercise

1. At rest - Increase HR as suppress parasympathetic 2. During exercise - Lower increase in HR, here sympathetic is dominant for increasing HR, hence less of a rise

Generation of a neuronal action potential

1. Depolarising stimulus - resting Na+ channels open, Na+ enters cell. 2. Inactivation - Na+ channels close, K+ channels open, K+ leaves cell. 3. Cell refractory state - Na+ channels restored to resting state but K+ channels still open so cell is refractory. 4. Resting state - Na+ and K+ channels restored to resting state. Therefore cell will respond normally to further depolarizing stimulus § These are all-or-nothing events, not like end-plate potentials in NMJs which are graded potentials.

Drugs which are commonly used to treat diseases of the respiratory tract can be grouped into one of four main categories (4)

1. Drugs which modulate the autonomic regulation (including those affecting second messenger systems) 2. Anti-inflammatory drugs 3. Anti-microbial drugs 4. Drugs used to treat cancer.

Clinical uses of benzodiazepines and barbiturates

1.ANAESTHETICS (barbs ONLY e.g. THIOPENTONE) 2.Anticonvulsants (diazepam (bzs); clonazepam (bzs); phenobarbital (barb)) - for epilepsy 3.Anti-spastics (diazepam) - works in spinal cord to reduce muscle tone and improve muscle functionality. 4.Anxiolytics 5.Sedatives / hypnotics

Strategies for minimising unwanted effects of drugs

1.Administer topically - fluid or foam enemas or suppositories 2.Use a low dose in combination with another drug 3.Use an oral or topically administered drug with high hepatic first pass metabolism e.g. Budesonide so little escapes into the systemic circulation

HIV life cycle

1.Attachment & Entry § Viral membrane proteins interact with leukocyte membrane receptors § Viral capsid endocytosis 2.Replication & Integration § Within cytoplasm - reverse transciptase enzyme converts viral RNA --> DNA § DNA transported into nucleus & integrated into host cell DNA. Once it is integrated, it cannot be removed, hence this is an incurable disease, can only maintain it. 3.Assembly & Release § Host cell's 'machinery' utilised to produce viral RNA & essential proteins § Virus is assembled within cell --> mature virion is released. **HIV is chronic disease, just need to take drugs. If have drug, have undetectable viral load and also will stop transmission of virus.

Anti-fungals: differentiate between the drugs used to treat fungal infections

1.Azoles - Inhibit ergosterol production 2.Polyenes - Bind to ergosterol and create pores

Classification of ADRs

1.Onset: a) Acute <1 hour. e.g. anaphylaxis b) Sub-acute 1-24 hours. c) Latent >2 days. 2.Severity: a) Mild no change in therapy required. b) Moderate change in therapy required, additional treatment and hospitalisation. c) Severe disabling, life-threatening, prolongs hospitalisation, causes congenital abnormalities, requires intervention to prevent further injury 3.Type: a) Type A: Augment/extend the pharmacological effect. § Usually predictable and dose-dependent, represents 2/3rds of ADRs. § Paracetamol has a threshold below which it has minimal side effects (and then exceeding this, side effects rapidly increase). Digoxin just has a dose-dependent line with constant increasing SEs. § E.G. Atenolol + heart block, NSAIDs + peptic ulcers. b) Type B: Bizarre - Idiosyncratic or Immunologic reactions. § Unpredictable, rare, and include allergy and "pseudo-allergy". § E.G. Chloramphenicol + aplastic anaemia, ACE inhibitors + angioedema. c) Type C: Chronic - Long-term use side effects. § Involves dose accumulation. § E.G. Methotrexate + liver fibrosis. d) Type D: Delayed - Delayed effects. § Carcinogenicity - e.g. immunosuppressants. § Teratogenicity - e.g. thalidomide. e) Type E: End of treatment side effects. BDP = benzodiazepines. § Withdrawal reactions - patient cannot make endogenous supply - opiates, corticosteroids, BDPs. § Rebound reactions - disease gets worse when drugs stopped - clonidine, b-blockers, corticosteroids. § "Adaptive" reactions - adapted body reactions to drugs - neuroleptics (tranquilis

Proportion of Drugs Metabolized by CYP450 Isozymes

3A4 most common then 2D6

Ritonavir is orally administered and absorbed in SI - identify all the phospholipid membrane barriers that need to be crossed before ritonavir can act to influence drug metabolism in the liver

7 in total. Intestinal epithelium apical membrane --> Intestinal epithelium basal membrane --> blood capillary membrane (x2) --> blood capillary membrane (x2) --> hepatocyte membrane

Cholesterol ester transfer protein (CETP) and reverse cholesterol transport

:§ CETP converts HDL into LDL and so inhibiting it increases HDL levels.

Which of the following effects would be observed with a non-depolarising neuromuscular block? A: Initial muscle fasciculations B: Irreversible nAChR blockade C: The block would be enhanced by anti-cholinesterase drugs D: A flaccid paralysis E: Increased arterial pressure

A flaccid paralysis

all pre ganglionic neurons release

ACh, acts on nicotinic receptors

Thrombosis: amplification stage

AMPLIFICATION STAGE: Cellullar level **Platelet activation & aggregation: 1.Thrombin •Factor IIa --> activates platelets 2.Activated platelet •Changes shape (distoid --> stellate) •Becomes 'sticky' and attaches other platelets

NSTEMI

Acute Coronary Syndrome - NSTEMI: § NSTEMI - Non-ST-Elevated MI. § Caused by - white thrombus - partially occluded coronary artery. o Damage to endothelium. o Platelet aggregation. o Atheroma formation. § Management: o Reduce lipid formation and platelet aggregation/activation - antiplatelets: § E.G. Clopidogrel, aspirin, Abciximab.

Relative selectivity of SNS agonists

All adrenoceptors can be activated by NA and A •Selectivity for Noradrenaline a1 = a2 > b1 = b2 •Selectivity for Adrenaline b1 = b2 > a1 = a2

Drug elimination interactions

Almost always in renal tubule: a) probenecid and penicillin (good) - Probenecid reduced excretion of penicillin and penicillin used to be expensive. b) lithium and thiazides (bad) - get increased excretion of sodium instead of lithium. thiazides lead to toxic accumulations of lithium.

Drugs for treating stable angina

Angina treatment - angina is a classic mismatch between myocardial supply and demand: § b-blocker or CCA - background first-line treatment (decrease HR and contractility); can combine these two as well. ** if CCA or beta blocker contraindicated: o Ivabradine - new more specific treatment. Acts on If. § Nitrate - releases NO. symptomatic treatment (i.e. exercise). § Other - e.g. K-channel openers if intolerant to other drugs e.g. nicorandil

Most recent anti-psychotic for Schizophrenia

Aripiprazole: o Partial agonist of D2 & 5-HT1A receptors - when too much activity, will decrease it; when little activity - will increase it. o No more efficacious than typical antipsychotics **Side effects: •Reduced incidences of hyperprolactinaemia & weight gain than other antipsychotics. Should increase compliance. First drug to have microchip that can monitor when it is taken.

HIV protease inhibitors

Assembly & Release § Gag precursor --> encodes all viral structural proteins § HIV protease cleaves Gag precursor protein. **Protease inhibitors (PI): a) Saquinavir - 1st generation PI b) Low dose Ritonavir reduces PI metabolism --> co-administered as 'booster'

MUSCARINIC RECEPTOR ANTAGONISTS - Clinical Use in Asthma

Asthma/ obstructive airway ddisease - block receptor that wants to constrict --> bronchodilation. Atropine is typical drug, ipratropium bromide is one used in asthma to try and localise effects to reduce side effects for systemic reach. it's more polar so can't cross lipid membrane.

Which of the following forms of drug antagonism describes the ability of adrenaline to reduce the effects of mast cell derived histamine during an anaphylactic response. A. Receptor blockade B. Physiological antagonism C. Chemical antagonism D. Pharmacokinetic antagonism E. Irreversible antagonism

B. Physiological antagonism. Physiological antagonism involves actions on different receptors causing opposite effects in same tissue: Adrenaline --> hypertension; histamine --> hypotension.

Drug metabolism often reduces the lipid solubility of drugs and thus makes the drug easier to excrete. Why is this so? A. Reduces distribution to the body fat B. Reduces reabsorption in the kidney C. Increases plasma protein binding D. Reduces the potency of the drug E. Enhances enterohepatic recycling

B. Reduces reabsorption in the kidney. If is lipid soluble will freely dissolve back into blood across conc gradient. If water-soluble - will remain in kidney tubules.

Which of the following is a side effect of atropine (a muscarinic antagonist)? A.Abdominal cramps B.Dilated pupils C.Bronchoconstriction D.Increased sweating E.Increased urinary frequency

B.Dilated pupils

Dobutamine

B1 agonist. β1>>β2>>>α1/2. - Clinical use: 1) Cardiogenic shock 2) Lacks isoprenaline's reflex tachycardia 3) Plasma half life 2 minutes (rapidly metabolised by COMT) - used as emergency medicine hence. quick effect. - no reflex tachycardia

Alcohol beneficial effects?

BENEFICIAL EFFECTS with low dose. ¯ decreased Mortality from coronary artery disease (Men 2-4 units/day); o increased HDLs o increased tPA level --> decreased platelet aggregation **due to polyphenols?? - so maybe wine > general alcohol effect. may reduce free radicals.

Vascular tone and BP

BP = CO x TPR § Arterioles contribute the greatest to blood pressure regulation. o SNS and other factors cause arteriolar constriction. o These vessels exhibit "vascular tone" and so always display a partial state of constriction. o Hypertensive patients tend to have a raised base vascular tone --> more TPR --> higher BP

Clearance

Blood (plasma) clearance is the volume of blood (plasma) cleared of a drug (i.e. from which the drug is completely removed) in a unit time (Related to volume of distribution and the rate at which the drug is eliminated. If clearance involves several processes, then total clearance is the sum of these processes.)

A 54-year-old man is admitted to Accident & Emergency suffering an anaphylactic reaction after being stung by a wasp whilst out rambling. The registrar finds a bottle of β-blocker tablets in his pocket. Which of the following clinical features of anaphylaxis could be worsened by these tablets? Bronchospasm & Hypertension/ Bronchospasm alone/ Hypertension alone/ Bronchospasm & Hyperglycaemia/ Urticaria

Bronchospasm alone

Which one of the following effects can be attributed to anti-cholinesterase poisoning? A. Bronchodilation B. Reduced gut motility C. Increased secretions D. Tachycardia E. Mydriasis

C. Increased secretions. Anti-anticholinesterase ---> build up of Ach --> more parasympathetic.

Which of the following neurones is associated with noradrenaline neurosecretion? A. Preganglionic sympathetic neurone innervating the sympathetic trunk B. Postganglionic sympathetic neurone innervating the kidney C. Sympathetic neurone innervating the adrenal medulla D. Postganglionic parasymapthetic neurone innervating the heart E. Postganglionic sympathetic neurone innervating the sweat gland

C. Sympathetic neurone innervating the adrenal medulla

Which ONE of the following statements about local anaesthetics is INCORRECT? They: A: Cause blockade of voltage-sensitive sodium channels B: Block rapidly firing neurones more readily than more slowly firing neurones C: Enhance action potential propagation D: Are largely ionised at physiological pH E: Have their durations of action increased if injected with adrenaline

C: Enhance action potential propagation

Which type of CCB for HT?

Calcium-Channel Blockers: E.G. Amlodipine, Verapamil. § Amlodipine is used to treat hypertension as it does not have an ionotropic effect on the heart. o DHPs inhibit Ca2+ entry into the VSMCs so less contraction of the cells --> less TPR --> less BP. o NOTE: powerful vasodilation can lead to a reflex tachycardia and increased ionotropy thus increased myocardial oxygen demand.

Glaucoma

Characterized by: Increase in intraocular pressure. Caused by: poor drainage of the aqueous humour by venous drainage channels. (produced by ciliary body to protect anterior chamber of eye). Often occurs with increased age. - If untreated, it permanently damages the optic nerve, blindness.

Pseudoallergies

Classifications - Type B ADR - Immunological "pseudo-allergies": not allergy. are a pharmacological reaction but associated with allergy symptoms. e.g. 1) Aspirin/NSAIDs - bronchospasm: Aspirin/NSAIDs inhibit COX so less prostaglandin synthesis and more leukotrienes made. 2) ACE inhibitors - cough/angioedema: o ACEi inhibit production of AngII and stop the breakdown of inflammatory mediators such as bradykinin which stimulate the cough receptors in the lungs.

Alpha antagonists examples

Clinical pharmacology 1) Non-selective a-blocker: phentolamine - used to treat phaechromocytoma-induced hypertension (tumour in adrenal medulla causing increased adrenaline) 2) a1 specific blocker: prazosin inhibit the vasoconstrictor activity of NE •Have modest blood pressure lowering effects •Only used as adjunctive treatment

Clinical use of cocaine

Clinical use: a) Local anaesthetic in ophthalmology (rare); do not coadminister with adrenaline. b) Well absorbed from all sites; readily crosses blood-brain barrier (unlike adrenaline and nor-adrenaline). c) Degraded by plasma esterases and hepatic enzymes; plasma half life approximately 30 minutes; excreted in urine.

Second generation antipsychotics used in treatment of Schizophrenia (1/3)

Clozapine: ØMost effective antipsychotic ØVery potent antagonist of 5-HT2A receptors ØOnly drug to show efficacy in treatment resistant schizophrenia & negative symptoms. **Side effects: •Can cause potentially fatal neutropenia, agranulocytosis, myocarditis & weight gain. Hence compliance of these drugs is very low.

Which enzyme is involved in metabolism of majority of drugs?

Cytochrome P450 enzyme

How long after smoking a cannabis cigarette will the effects persist in the body? A)5 hours B)12 hours C)7 days D)30 days E)10 years

D- 30 days. o 1 dose persists for at least 5 days o levels detectable 30 days after smoke cannabis. o can test cannabis through hair testing.

Tricyclic antidepressant drugs (TCAs) work largely by: A: Antagonism at 5HT receptors B: Inhibiting central DA reuptake C: Blocking VSCCs D: Inhibition of central NA & 5HT reuptake E: Enhancement of the action of GABA

D: Inhibition of central NA & 5HT reuptake

Lidocaine: A: Inhibits reuptake of 5-hydroxytryptamine B: Blocks voltage-gated K+ channels C: Is a competitive muscarinic cholinoceptor antagonist D: Is a weak base E: Is a general anaesthetic

D: Is a weak base

Two main classes of anti-fungals

Drug details: •15 anti-fungal drugs licensed in the UK •Two most common categories: 1.Azoles: Fluconazole 2.Polyenes: Amphotericin **Azoles: § Inhibit cytochrome P450-dependent enzymes (esp. Cyp51p enzymes) involved in cell membrane sterol synthesis. § e.g.Fluconazole (oral) --> candidiasis & systemic infections **Polyenes: § Interact with cell membrane sterols forming membrane channels. Disruption of homeostasis of cell. § e.g. Amphotericin (I-V) --> systemic infections

Physostigmine

E.g. of Reversible anticholinesterase drugs •Naturally occurring tertiary amine from Calabar beans •Primarily acts at the postganglionic parasympathetic synapse (t1/2 ≈ 30 mins) •Used in the treatment of glaucoma, aiding intraocular fluid drainage •Also used to treat atropine poisoning (as competing for Ach), particularly in children

Which of the following drugs is commonly used in the treatment of insomnia? A: Thiopental B: Phenytoin C: Baclofen D: Sodium valproate E: Temazepam

E: Temazepam

What's the problem with excretion of drug via bile in liver?

Enterohepatic cycling - drug/metabolite excreted into gut (via bile) then reabsorbed, taken to liver and excreted again... leads to drug persistence. Process: hepatocytes make water-soluble conjugates to excreted in bile --> ends up in gut, gut bacteria break down conjugate and get free drug release and fat-soluble form and then diffuses back across capillaries into HPV and into liver.

Epilepsy aetiology

Epilepsy aetiology is either: a) idiopathic (normal brain - i.e., no cause found other than a suspected inherited predisposition). b) symptomatic (the epilepsy is a symptom of an underlying cerebral injury - usually stroke, trauma or tumour). c) cryptogenic (where an underlying brain injury is suspected but not identified). In general, the cryptogenic category is diminishing, as our understanding of epilepsy advances and the quality of neuroimaging improves.

Carbamazepine enhances the activity of warfarin. True/ False

False

Losartan and candesartan are both pro-drugs (Angiotensin II receptor blockers). What do you understand by this term?

For both losartan and candesartan, the parent compounds have little or no clinical efficacy. The parent compounds need to be metabolised in order to liberate the active metabolite responsible for the therapeutic effect. In the case of losartan, the metabolite is produced by metabolism in the liver, whereas candesartan is metabolised as it is absorbed from the gut. It is the active metabolite that then blocks the angiotensin receptor within the tissues.

What type of receptors are adrenoreceptors?

G-protein coupled receptors

All NSAIDS increase risk of what?

GI bleeding and CV event. o ibuprofen is lowest risk of both § COX-1 inhibition --> increased GI risk. § COX-2 inhibition --> increased CVS ris

MUSCARINIC RECEPTOR ANTAGONISTS - Clinical Use in IBS

GIT - IBS. Parasympathetic stimulates motility and tone. so try to slow gut down. M3 receptor antagonist to try and limit effects of IBS.

Generally, IV GAs are much more ____ and the inhaled GAs are much more ____ but equally as potent.

Generally, IV GAs are much more selective and the inhaled GAs are much more non-selective but equally as potent.

Drug tolerance definition

Gradual decrease in responsiveness to drug with repeated admin. (days/weeks) e.g. benzodiazepines for epilepsy

Which bacterium is responsible for causing the majority of peptic ulcers? Acinetobacter baumanii/ Staphylococcus aureus/ Escherichia coli/ Mycobacterium tuberculosis/ Helicobacter pylori

Helicobacter pylori

GERD

In this condition stomach and duodenal contents reflux into the oesophagus.

The antiplatelet drug clopidogrel acts by what mechanism of action? Inhibition of vitamin K produced by platelets/ Inhibition of the protease-activated receptor on platelets/ Inhibition of thromboxane A2 production in platelets/ Inhibition of an ADP receptor on platelets/ Inhibition of the glycoprotein IIb/IIIa receptor on platelets.

Inhibition of an ADP receptor on platelets

Ritonavir is one of the anti-HIV drugs taken by Mr Johnson and is orally administered. Identify all the membrane barriers that need to be crossed before ritonavir can act to influence drug metabolism.

Intestinal epithelium apical membrane --> Intestinal epithelium basal membrane --> blood capillary membrane (x2) --> blood capillary membrane (x2) --> hepatocyte membrane

Where is the major site of drug metabolism in body?

Liver. o The major site of metabolism of foreign chemicals/xenobiotics in man is the liver. Cytochrome P450 enzymes for a central part of the drug metabolising system and are found in the SER. Its principal role is in oxidation of chemicals and hence requires oxygen and the coenzyme NADPH. o Phase 1 metabolism typically involves oxidation or reduction reactions. Give two examples; deamination and hydroxylation. o Phase 2 metabolism typically involves conjugation reactions which increase the polarity of drugs which facilitates excretion. o Give two examples; glucuronidation and acetylation. o Glutathione is a tripeptide consisting of glutamine, cysteine and glycine which is most abundant in the liver and reacts with electrophilic chemical intermediates.

Loop diuretics acute and chronic treatment of HF

Loop diuretics: § Acute reduction in congestion. o But will increase renin secretion --> cardiac remodelling. § Chronic use is associated with resistance and RAS activation. o Additional use of K+ sparing diuretics is used to try to stop the rebound activation of RAS.

Loop diuretics and potassium sparing diuretics for treatment of HF.

Loop diuretics: § Acute reduction in congestion. o But will increase renin secretion --> cardiac remodelling. § Chronic use is associated with resistance and RAS activation. o Additional use of K+ sparing diuretics is used to try to stop the rebound activation of RAS. (e..g spironolactone) - reduces risk of death

Which antihypertensive medication will reduce vasoconstriction by inhibiting a G-protein coupled receptor found on vascular smooth muscle? Nicardipine (calcium channel blocker) Ramipril (ACE inhibitor) Atenolol (beta-blocker) Bendroflumethiazide (thiazide) Losartan (angiotensin receptor blocker)

Losartan (angiotensin receptor blocker)

Which class of antibiotic drug inhibits the bacterial ribosomes? Fluoroquinolones/ Rifamycins/ Penicillins/ Cephalosporins/ Macrolides.

Macrolides

Paracetomal to NAPQ1

NAPQI is electrophilic and will be further metabolised and detoxified by a phase 2 reaction

why is suxamethonium used in ECT?

NM blocking drug that stops them convulsing during therapy. Short-acting for 5-6 mins

IV administration pros and cons

Pros: 1) rapid onset of action 2) avoids poor absorption from, and destruction within, the g.i. tract permits careful control of blood levels Cons: 1) slow injection necessary (to avoid toxic bolus) higher incidence of anaphylactic shock 2) trained personnel required 3) complications possible; embolism, phlebitis, pain

Which neurological pathways are thought to be involved in the aetiology of the various aspects of schizophrenia?

See diagram - Pathways A & C linked to the positive and negative symptoms of schizophrenia.

Despite her medical condition, Gemma is a keen hockey player, who plays for her university team and is determined not to let her respiratory condition hold her back. What simple precautions would you advise her to take before playing hockey?

Take her normal bronchodilator (brown steroid inhaler (dexamethasone)) and do a warm up before exercising. The doctor may prescribe a long- acting bronchodilator such as salmeterol to build up a good level of "cover"

What is pharmacokinetics?

The journey of a drug through the body

What are main mechanisms described for drugs in current clinical use for epilepsy?

The main mechanisms described for drugs in current clinical use: 1) Interaction with voltage-dependent sodium channels 2) Direct or indirect enhancement of GABA transmission 3) Interaction with neuronal calcium channels 4) Blocking receptors for excitatory neurotransmitters

Pros and cons of oral route of administration

The oral route for administration of medicines is the most common and convenient. It has advantages: 1) It permits self-medication 2) It does not require rigorously sterile preparations 3) The incidence of anaphylactic shock is lower (than intravenous) 4) There is the capacity to prevent complete absorption (vomiting, lavage). oHowever, disadvantages are that: 1) It is inappropriate for drugs which:are labile in acid pH of stomach or otherwise degradedor undergo extensive 'first-pass' metabolism, 2) It requires patient compliance.

Nervous Control of the Airways

The tone of the bronchial muscle is controlled by autonomic nerves. Because the bronchial muscle is arranged in a circular fashion around the bronchi, the degree of tone has a significant effect on airway resistance. Dilatation of the bronchi in a normal individual decreases resistance by 25% and bronchoconstriction increases airway resistance. The resistance to airflow is inversely proportional to the fourth power of the airway radius, so a small change in airway diameter can have a large effect on resistance and hence on the difficulty of breathing. o A variety of diseases can reduce the airway diameter and hence increase airway resistance in a variety of ways, the most common being asthma (mucus plugs, bronchoconstriction), fibrotic lung conditions (reduce lung volumes and put pressure on the airways) and inhaled foreign bodies (especially in children).

Apparent volume of distribution

The volume in which a drug appears to be distributed - an indicator of the pattern of distribution

Common viral infections treated using chemotherapy

There are currently around 50 licensed antiviral agents and almost half of them are used for the treatment of Human Immunodefi-ciency Virus (HIV). The other antivirals are primarily used in thetreatment of Hepatitis B virus (HBV), Hepatitis C virus (HCV), herpesvirus and influenza virus. 1) HIV 2) Hepatitis 3) Herpesvirus 4) Influenza

Schematic plan for vomiting pathways and stimuli

These drugs are indicated ONLY when the cause of the nausea/vomiting is known, otherwise they mask the diagnosis of potentially serious conditions, e.g. digoxin excess, diabetic ketoacidosis

Different mechanisms of transfer across membranes

Transfer across membranes may occur by one or more of six possible mechanisms: 1. passive diffusion (most common - pH PARTITION HYPOTHESIS) 2. facilitated diffusion 3. active transport (more important in drug excretion) 4. pinocytosis (phagocytosis-like mechanisms - liposomes) 5. filtration (small water soluble molecules) 6. paracellular transport (around cells, often overlooked).

Blockade of which of the following targets would cause the most significant rise in synaptic noradrenaline concentrations? 1.Tyrosine hydroxylase 2.DOPA decarboxylase 3.Uptake 1 transport protein 4.Monoamine oxidase 5.Cathecol-O-methyl transferase

Uptake 1 transport protein

Opioids - urticaria

Urticaria (Local Inflammation): § Not all opioids cause histamine release - it is the hydroxyl group found on some opioids that cause mast cell degranulation (non-IgE-mediated) causing histamine release. o You can switch people to different opioids if they display this response (one without the OH group). § This reaction is PKA mediated (not receptor-mediated).

D-dimer testing

Utilized for the diagnosis of deep vein thrombosis (DVT) and pulmonary embolism. Test for fibrin degradation products within blood; likely to be present if someone has a clot.

Vasodilators agents

a. Calcium channel antagonists b. Hydralazine, nitroprusside and (organic nitrates*), (potassium channel openers*) c. Alpha blockers and sympatholytics

Two other drug classes are commonly utilised in the treatment of glaucoma - the prostaglandin analogues (e.g. latanoprost) and the carbonic anhydrase inhibitors (e.g. acetazolamide). Why are these two drug classes effective treatments for glaucoma?

a. Prostaglandin analogues - improve drainage, increase the enzymes that break down collagen. b. Carbonic anhydrase inhibitors - reduce production of aqueous humour, reduce bicarbonate production and that is part of the aqueous humour.

Which of the following drugs has efficacy for the muscarinic acetylcholine receptor? A.Acetylcholine B.Atropine C.Acetyl-cholinesterase D.Adrenaline E.Acetate

acetylcholine

NTs of parasympathetic (craniosacral)

ach; long pre ganglionic neurone

Explain in your own words, what you understand by the terms 'affinity' and 'efficacy'. Briefly explain what you understand by the term 'structure-activity relationship' and how might this relate to affinity and efficacy.

affinity - measure of strength of drug binding to receptor; efficacy - measure of ability once drug is bound, hence generating a response. depending on structure of drug, the activity is dependant.

MUSCARINIC RECEPTOR ANTAGONISTS - Clinical Use in anaesthetics

anaesthetic premedication - blocks production of saliva (so no secretions to block airway), blocks heart rate and contractility, blocks trachea and bronchioles and sedation (e.g. with hyoscine). blocks parasympathetic effect

Explain how an opioid antagonist, naloxone, could restore someone back to consciousness after taking fentanyl. Differentiate between the four principal types of drug antagonism

antagonist opposes agonist, shifts D-R curve to the right they have affinity but no efficacy four types - receptor blockade, chemical antagonism (anti-venom), physiological (allergic reaction given adrenaline), pharmacokinetic (increased metabolism)

How do most venoms affect CNS?

are NICOTINIC RECEPTOR ANTAGONISTS

Glaucoma treatment

b1 blocker - decrease production of aqueous humour by ciliary body - stops production of bicarbonate ions that are used to produce aqueous humour. other option is to increase drainage. Produced by blood vessels in ciliary body via the actions of carbonic anhydrase. Flows into posterior chamber, through the pupil to anterior chamber. Drains into trabecular network and into the veins and canal of Schlemm. Production indirectly related to blood pressure and blood flow in ciliary body

Aspirin is unique amongst NSAIDS because: a)It has no effect on COX-1 b)It has no effect on COX-2 c)It binds covalently to COX enzymes d)It binds covalently to TP receptors e)It causes gastric ulceration

c)It binds covalently to COX enzymes

Partial agonist dose response curve

can never generate full response but also have some antagonist activity when administered with full agonist

Which of the drugs in this table would see plasma concentrations increase the most if co-administered with ritonavir?

carbamazepine (only one that is metabolised by only one enzyme)

Motor neurone is what type of neurone?

cholinergic

Which antipsychotic drug is associated with neutropenia and agranulocytosis?

clozapine

NAPQI is electrophilic and will be furthered metabolised and detoxified a by a phase 2 reaction, discuss this reaction

conjugated with glutathione. by doing this, restore aromicity - looks like paracetamol again

How do we convert paracetamol to an electrophile?

drug needs to be electrophilic to be conjugated or biotransformed to an electrophilic conjugate in phase 2 metabolism. So how do we convert paracetamol to an electrophile? it undergoes oxidation and loses a hydrogen (phase 1 metabolism) to form NAPQ1 before undergoing glutathione conjugation (phase 2 metabolism). glutathione conjugation however does not occur when we use up glutathione stores which occurs when there is paracetamol overdose. then we are left with very reactive phase 1 metabolite (NAPQ1) which can cause lots of damage to liver proteins and cause dysfunction.

In IBD, budesonide causes fewer unwanted systemic effects than prednisolone because: a.It can be administered topically b.It can be co-administered with another drug c.It has a higher potency at therapeutic doses d.It has a lower potency at therapeutic doses e.It is metabolised and inactivated locally

e. It is metabolised and inactivated locally

Ecothiopate

e.g of Irreversible Anticholinesterase Drugs •Potent inhibitor of acetylcholinesterase •Slow reactivation of the enzyme by hydrolysis takes several days •Used as eye drops in treatment of glaucoma, acting to increase intraocular fluid drainage with a prolonged duration of action •Systemic side effects: sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty

Why are non-ergot derivative DA agonists recommended over ergot derivatives?

ergot derivatives are associated with cardiac fibrosis

Generally muscarinic receptors are what?

excitatory, except with heart - it slows down heart

ACE inhibitors are never given in conjunction with beta-blockers. True or False?

false

Regarding ethanol metabolism: Acetate is a toxic end-product of ethanol metabolism. True/ False

false

As a drug class - what is onset and DOA of epileptic drugs?

fast onset of action and long duration of action.

The following diagram shows three log dose-response curves for three different drugs- A, B and C. What could the curve labelled B represent?

full agonist in the presence of a competitive agonist. eventually reaches max as it is surmountable

What is most common phase 2 metabolism reaction?

glucuronidation

what amino acids make up glutathione?

glutamate, glycine, cysteine

Muscarinic Cholinergic Target Systems

high density in eye, salivary glands, sweat glands, lungs, heart, gut, bladder, vasculature

Where does phase 1 metabolism occur on aspirin?

hydroxylation on the side O group --> this reactive OH can now conjugate

MUSCARINIC RECEPTOR ANTAGONISTS - Clinical Use in motion sickness

hyoscine patch. motion sickness is sensory mismatch; when visual info from eyes and labyrinth from ear relaying balance, mismatch, get vomiting which is transmitted by cholinergic nerve to vomiting centre. so hyoscine would diffuse into bloodstream, into vomiting centre and block the muscarinic receptor

'Potency' of a drug depends on:

i) Affinity (binding property of receptor - avidity as well) ii) Efficacy ('intrinsic activity') Þ conformational change of receptor - IM forces and affinity makes it join together, then forms complex, and then to get a response, need to have an intrinsic efficacy which involves some kind of transducer system

Indirectly Acting SNS Agonist: Tyramine:

i.e. the drugs themselves do not act at the adrenoceptors o TYRAMINE a dietary amino acid found in foods such as cheese, red wine and soy sauce. § Also known as the "cheese reaction". § Tyramine acts as a false neurotransmitter. o This is usually not a problem when the normal mechanisms for degradation of MAO are in place. o We used to prescribe MAO inhibitors as anti-depressants. 1. Weak action at the receptors for NA. 2. Weak inhibitory effect on the uptake 1. 3. Displaces NA from the vesicles. 4. Competes for MAO breakdown so less breakdown of NA. 5. Leakage of NA out of the vesicles. Inhibited MAO means that tyramine administration can then compete with any MAO left and lead to a massive hypertensive crisis when NA build-up is more than usual.

Why might treatment with IV sodium bicarbonate increase aspirin excretion?

increases urine pH, hence pH increases and more in ionised form, filtered through kidney tubules and stays in urine and is excreted.

intrafusal fibers vs extrafusal fibres

intra - modified muscle fibers within the spindle; extra - power producing muscle fibres external with respect to muscle spindles

Glucuronidation is what type of reaction?

low affinity/ high capacity - more likely to occur at high drug dosages

The following graph shows the increase in the plasma concentration of three different statins (pravastatin, atorvastatin and simvastatin) after co-administration with ritonavir. Interpret the graph

metabolism of atorvastatin is impaired by ritonavir

Alcohol consumption epidemiology

more in western europe, Greenland and Russia.

Based on the metabolic products of paracetamol stated above, suggest what could be used to salvage the toxicity in a case of acute poisoning and explain your mechanistic reasoning.

n-acetyl cysteine - won't be used for protein synthesis along gut or liver. key susbtrate needed for glutathione synthesis. could give methionine or SAM. glutathione is given to neutralise NAPQI, as this also has sulphur in cysteine, can also help with sulphation reactions

Why is bioequivalence important when prescribing generic versions of a drug which have a narrow therapeutic index?

need to make sure are in the range of ED50 and TD 50

Paracetamol is an NSAID?

no. •Is a widely used effective analgesic for mild-to-moderate pain which is available over the counter •Has anti-pyretic action •Has minimal anti-inflammatory effect •Therefore it is not a NSAID

Certain β-blockers may produce adverse effects in some people. What are these likely to be?

non-selective ones. block beta 1 and beta 2. if block them, can get bronchoconstriction hence wouldn't give to asthmatics. beta 2 receptors on liver - gluconeogenesis --> hence wouldn't give to diabetics. don't give to pregnant women as it can pass through placenta

Noreadrenaline metabolism

noradrenaline controls it's own secretion so don't get excessive NE effect. an agonist acting on prejunctional receptor will reduce NE effect. § Noradrenaline remember is made in nerve terminals whereas adrenaline is synthesised in the adrenal medulla. § Noradrenaline metabolism is displayed in pic o Tyr --> DOPA --> DA --> NE. o NE binding to prejunctional a2 adrenoceptors negatively feedbacks on NE exocytosis.

Drug interactions of MAOIs

o "Cheese reaction" - Tyramine-containing foods + MAOI --> hypertensive crisis. (throbbing headache, b.p., intracranial haemorrhage). § Tyramine is metabolised by MAO and so high levels of tyramine compete with NA and so higher levels of NA leading to the hypertensive episodes. o MAOIs + TCAs --> hypertensive episodes. o MAOIs + pethidine --> hyperpyrexia, restlessness, coma & hypotension. *hence need to limit tyramine-rich foods- marmite, mature cheeses, game, red wine. * Moclobemide - reversible, selective MAO-A inhibitor (RIMA - Reversible inhibitor of MOA-A) --> reduced drug interactions and reduced DoA.

4 main outcomes to schizophrenia:

o 10-20% = Illness resolves completely (with or without treatment). o 30-35%= Illness recurs repeatedly with full recovery after each episode. o 30-35% = Illness recurs repeatedly with incomplete recovery and increasing defective states. o 10-20% = Illness has a rapidly downhill course.

Alcohol dehydrogenase levels in men vs women

o 15% metabolism in GIT. o women have 50% less alcohol dehydrogenase than men, hence less ability to metabolise alcohol. § GIT Metabolism: o Alcohol --> acetaldehyde (toxic) via: § 100% - Alcohol dehydrogenase - found in the stomach. · Females have 50% less ADH than males in the GIT.

Aminosalicylates MOA

o 5-ASA binds to PPAR receptors, acts as transcription modulator and can downregulate NF-kB/MAPK --> decrease pro-inflammatory cytokines (e..g TNF-a); also downregulates COX-2 --> decrease prostaglandins (e.g. PGE2) o Anti-inflammatory activity and interfere with the production of cytokines, free radical scavenger, etc

Label the letters A-H as shown on the diagram with either the neurotransmitter or hormone released from each site or the receptor which is stimulated at each site.

o A = Acetylcholine (ACh) o B = Nicotinic ACh receptor o C = ACh o D = Muscarinic receptor o E = ACh o F = Nicotinic ACh receptor o G = Adrenaline o H = Beta2-adrenergic receptor

Alcohol Acute effects: Endocrine system

o ADH (Alcohol dehydrogenase) supresses VP release. Direct inhibitory action at hypothalamus o Less VP and less water reabsorption --> diuresis. o thought to be due to acetaldehyde

Antidote for paracetamol poisoning

o Add a compound with an -SH group. 1) IV Acetylcysteine - used in cases of attempted suicide. · If not administered early enough, liver failure may be unpreventable. 2) Oral methionine. **now legislation to prevent overselling

Pros and cons of Percutaneous - across the skin

o Advantages 1) local application and action 2) lipid soluble compounds diffuse rapidly (may be assisted by vehicles) o Disadvantages 1) local irritation and skin reactions 2) alteration of skin structure (e.g. steroids - subcutaneous adipose tissue)

Two types of antagonists

o Affinity but NO efficacy 2 types of receptor antagonist: 1. Competitive Þ same site as agonist Þ surmountable (can overcome it if add more substance) Þ shifts D-R curve to RIGHT Examples : competitive atropine muscarinic, propranolol (beta blocker, antihypertensive, antiarrhythmia, prophylaxis of migraine) 2. Irreversible Þ binds tightly OR at different site Þ insurmountable Example: hexamethonium.

Cardiac Inotropes

o Agents that the force of cardiac contraction are used to treat acute heart failure in some situations (e.g. after cardiac surgery or in cardiogenic or septic shock). Dobutamine is a β1 adrenoceptor agonist that can be used for this purpose to stimulate cardiac contraction as it doesn't have too marked an effect on heart rate. o The endogenous peptide hormone, glucagon is an alternative. Inhibitors of phosphodiesterase, the enzyme that metabolizes cAMP, such as milrinone, have inotropic effects but despite increasing cardiac function in heart failure actually impair survival and at present inotropes are not used in chronic heart failure.

receptors in role of arrhythmias

o An increase in sympathetic drive to the heart via b1 can precipitate or aggravate arrhythmias. Particularly after myocardial infarction there is an increase in sympathetic tone. o AV conductance also depends critically on sympathetic activity, and the refractory period of the AV node is increased by b-adrenoceptor antagonists, interfering with AV conduction in atrial tachycardia's, and to slow ventricular rate. in arrhythmia try to slow heart down and get more blood flow from atria to ventricles. hence use beta blockers to get more normal rhythym. USE PROPANOLOL (b1) generally to treat.

Examples of 'Non-specific' drug action

o Antacids - addition of a base to the acidic environment which evens acid-base balance. Mainly salts of Al3+ and Mg2+ that neutralize acid, raise gastric pH and reduce pepsin activity. o Osmotic purgatives (laxatives) - draws water into the gut to decrease viscosity. N.b. - Plasma protein binding (PPB) - Some drugs bind very strongly to plasma proteins and so can provide a dangerous and untapped reservoir of the drug (e.g. warfarin).

Biologic therapies for IBD

o Approved for use in IBD: Ø Anti- TNFa antibodies main one. Ø Example: Infliximab (iv) Ø Other antibodies effective but some have more side-effects Ø New humanised antibodies coming on stream eg Entanacept (more control of S/E) **useful thing about infliximab is that it works on TNF-a bound to cell membranes and already solubilised. mops up TNF-a and stops it binding to receptors, hence breaking cascade: ØAnti- TNFa reduces activation of TNF a receptors in the gut ØReduces downstream inflammatory events ØBinds to membrane associated TNFa ØInduces cytolysis of cells expressing TNFa ØPromotes apoptosis of activated T cells

Unwanted effects of MAOIs

o Atropine-like effects (anti-PNS effects) - but less so than TCAs. o Postural hypotension - common. o Sedation - causes seizures in OD. o Weight gain - possibly excessive. o Hepatotoxicity - due to hydrazine side group, rare.

Side effects of beta blockers

o Bronchoconstriction - Asthma/COPD o Cardiac Failure - Need some sympathetic drive to the heart o Hypoglycemia - Mask the symptoms of hypoglycemia/inhibit glycogen breakdown o Fatigue - decreased cardiac output and decreased muscle perfusion. o Cold Extremities - Loss of b-receptor mediated vasodilatation in cutaneous vessels. o Bad Dreams - central effects of beta blockers too

Glaucoma characterised by and caused by...

o Characterized by: Increase in intraocular pressure. o Caused by: poor drainage of the aqueous humour. If untreated, it permanently damages the optic nerve, blindness - two things that increase aqueous humour in eye: a) Reduced drainage b) Ciliary body production (Produced by blood vessels in ciliary body via actions of carbonic anhydrase.) o Production is indirectly related to BP. o Flow: posterior chamber --> through pupil to anterior chamber --> trabecular meshwork and into veins and canal of Schlemm.

Cocaine Pharmacodynamics - Cardiovascular: Myocardial Infarction

o Cocaine stimulates the sympathetic nervous system by inhibiting catecholamine reuptake at sympathetic nerve terminals, stimulating central sympathetic outflow, and increasing the sensitivity of adrenergic nerve endings to norepinephrine. o Cocaine also acts like a class I antiarrhythmic agent (local anesthetic) by blocking sodium and potassium channels, which depresses cardiovascular parameters. o Of these 2 primary, opposing actions, enhanced sympathetic activity predominates at low cocaine doses, whereas the local anesthetic actions are more prominent at higher doses. o In addition, cocaine stimulates the release of endothelin-1, a potent vasoconstrictor, from endothelial cells and inhibits nitric oxide production, the principal vasodilator produced by endothelial cells. o Cocaine promotes thrombosis by activating platelets, increasing platelet aggregation. ** **o Increased catecholamines, decrease sodium transport (LA), can induce inflammation chronically and increased sympathetic drive on the heart increases oxygen demand on the heart. o Hence see sympathetic effects... a) platelet activation b) Vasoconstriction decreases delivery of oxygen to the heart. c) Increase HR, contractility, BP o These can lead to endothelial injury and atherosclerosis (less myocardial o2 supply to o2 demand) --> result is ischaemia of the heart muscle --> (combined with decreased sodium transport and decreased ventricular function) arrythmias and sudden death

Treatment for stroke

o Diagnosis & Treatment: •Ischaemic stroke •Thrombolytic therapy --> ALTEPLASE (tPA) (thrombolytics usually only given in emergencies)

Dosing of cannabis

o Doses in 60's and 70's was ~10mg THC. o Now it is 150-300mg of THC. o Potency has increased over the years and this means if delta9-THC has increased, so has cannabidiol. o This is relevant because as delta9-THC increases, potentially, the negative effects are more pronounced than the positive effects. potentially because lost cannabidiol (positive effect) to increase delta9-THC. ** in medical students: 46% tried it at some point; 10% regular users. in failing students, regular cannabis users 89% likely to fail vs 39% normally.

Enteral vs Parenteral administration

o Enteral - Gastro-intestinal administration. o Parenteral - Outside the GI tract. mainly by mouth § IV administration has a rapid onset of action but is invasive and requires training. e.g. inhalation, IV

Why don't give SSRIs and TCAs together

o Fluoxetine (SSRI) competes with TCAs for hepatic enzymes so avoid co-administration. **also interacts with MAOIs - avoid co-administration.

Why might I.V Sodium Bicarb increase aspirin excretion?

o I.V. Sodium Bicarbonate increases urine pH. o Increase in urine pH ionises the aspirin. o This makes it less lipid soluble. o Less aspirin is reabsorbed in the proximal and distal tubules. o Increase in the rate of excretion of aspirin.

Effects of Tubocurarine

o Naturally occuring 4° ammonium compound (alkaloid) found in S. American plant (arrow poison) o Range of synthetic drugs now available * MOA - COMPETITIVE nachr ANTAGONIST - 70 - 80% block necessary to get paralysis so EP potential is then insufficient * EFFECTS - Tubocurarine --> flaccid paralysis Extrinsic eye muscles (double vision) --> Small muscles of face, limbs, pharynx --> Respiratory muscles * order of recovery is in reverse. *USES - Relaxation of skeletal muscles during surgical operations (= less anaesthetic and procedure is safer) esp. in abdominal surgery - Permit artificial ventilation * N.B. - Actions of NON-depolarising blockers can be reversed by ANTICHOLINESTERASES (so raise endogenous Ach and can overcome competitive tubocurarine) - Neostigmine is an anticholinesterase (2-3 hours lasting) (+ atropine to damp down overstimulation of muscarinic receptors) * PHARMACOKINETICS - Roa = i.V. (Highly charged) - Does NOT cross bbb or placenta - so can be used safely in obsetrics - Duration of paralysis: 1 - 2 hr (long) - Not metabolised - Excretion: 70% urine; 30% bile (care if renal or hepatic function impaired) - hence would take longer to be excreted; hence would use this drug Atracurium (15 min; chem. Unstable) - same mechanism but short half life - is hydrolysed in plasma after 15 mins * UNWANTED EFFECTS: (GANGLION BLOCK; HISTAMINE RELEASE) a) HYPOTENSION •Ganglion blockade (decreases tpr) in other receptors •Histamine release from mast cells - as tubocurarine is so basic; is vasodilator and decreases TPR b) TACHYCARDIA (MAY -->ARRHYTHMIAS) •Reflex to drop in BP •Also from blockade of vagal ganglia c) BRONCHOSPASM - due to histamine release d) EXCESSIVE SECRETIONS (BRONCHIAL & SALIVARY) - due to histamine release e) APNOEA (ALWAYS ASSIST RESPIRATION)

What is pharmacogenetics and pharmacogenomics?

o pharmacogenetics - study of genetically determined inter-individual differences in therapeutic response to drugs and susceptibility to adverse effects. restricted to one or few genes of interest. mendelian segregation. o pharmacogenomics - use of genome-based techniques in drug development. not restricted to one or few genes. use of high-throughput technologies.

Clonidine withdrawal

o start off with hypertensive, treat them and BP decreases. o when stop drug, get a rebound reaction where BP goes higher than initially. o may lead to stroke or death.

Enteric NS under control of which NS?

o symp, parasymp and local a) Sensory neurone connected to mucosal chemoreceptors and stretch receptors detect chemical substances in the gut lumen or tension in the gut wall caused by food. b) Information relayed to submucosal and myenteric plexus via interneurons. c) Motor neurones release acetylcholine or substance P to contract smooth muscle; vasoactive intestinal peptide or nitric oxide to relax smooth muscle.

Aminosalicylates 2 examples

o symptomatic treatment for IBD: mesalazin (aka 5- ASA) OR Olsalazine

Pharmacokinetics: administration routes

oral, dermal, IM, IV, subcutaenous, inhale, ingestion, intraperitoneal. Can get SYSTEMIC or LOCAL effect. § Sites used for administration are: o Enteral - Gastro-intestinal administration. e.g. sublingual, buccal, oral, rectal. o Parenteral - Outside the GI tract. mainly by mouth e.g. intravenous, intramuscular (DEPOT THERAPY), subcutaneous, percutaneous, inhalation. § IV administration has a rapid onset of action but is invasive and requires training. e.g. inhalation, IV

Suxamethonium is a depolarising neuromuscular blocker commonly used to relax the airways during endotracheal intubation. How does suxamethonium relax the airways?

overstimulation of nAchR, preventing the myocytes from relaxing. Topic Summary: There are 2 types of neuromuscular blocking drugs-Non depolarising neuromuscular blockers are competitive antagonists, whilst depolarising neuromuscular blockers are agonists. These drugs do not affect consciousness and pain sensation but affect the respiratory muscles so respiration must always be assisted until the drug is inactive or antagonised.

What is ion trapping (pH partitioning)?

pH may differ on two sides of a membrane and drugs will accumulate on the side of the membrane favouring their ionisation. Ionised form can't diffuse well when crossing lipid membranes. HINT: Blood is slightly alkaline. hence always need to know pKa of drug

Hardy-weinburg equation

p^2 + 2pq + q^2 = 1

pharmacokinetics vs dynamics

pharmacokinetics: effect of body on drug e.g. excretion pharmacodynamics: effect of drug on body e.g. mechanism of action

A 7-year-old presents to the emergency department with vomiting, agitation and fever after eating some berries whilst walking in the woods. The doctor suspects atropine poisoning. What would the first-line treatment for this child? Physostigmine (reversible anticholinesterase) Trimetaphan (Ganglion blocking drug) Bethenacol (M3-selective muscarinic receptor agonist) Ecothiopate (Irreversible anticholinesterase) Pilocarpine (non-selective muscarinic agonist)

physostigmine (reversible anticholinesterase). Topic summary: Atropine poisoning is particularly common in children. Atropine is a competitive muscarinic antagonist meaning that it is surmountable. Therefore, to combat the effect of muscarinic blockade the synaptic concentration of Acetylcholine should be increased.

Which drug is used to treat atropine poisoning?

physostigmine (reversible anticholinesterases: competitive antagonism). **Physostigmine: •Primarily acts at the postganglionic parasympathetic synapse (t1/2 ≈ 30 mins) •Used in the treatment of glaucoma, aiding intraocular fluid drainage •Used to treat atropine poisoning

A patient being prescribed atropine (muscarinic receptor antagonist) complains of very dry skin and getting increasingly hot flushes whilst exercising. The effects of which autonomic neurone are being blocked to cause these specific symptoms?

post-ganglionic sympathetic Topic Summary: The symptoms the patient is experiencing indicate they are not sweating-in other words there is reduced activity of the sweat glands. The sweat glands are innervated by the sympathetic nervous system; however, they are an exception as they do not have adrenoceptors on their surface

What type of thrombus formed in DVT?

red thrombus. § DVT - a red thrombus of the deep veins of the leg (e.g. popliteal vein). o Caused by - stasis of blood and damage to endothelium. § PE - thrombus detachment. § Management: o Reduce levels of anticoagulant factors - anticoagulants. § E.G. Dabigatran, Rivaroxaban, Heparin, Warfarin.

Chronic use of loop diuretics in treatment of HF associated with...

resistance due to RAS activation... hence fix this with additional use of potassium sparing diuretics (so reduce the Na/K exchange and reduce sodium and water Loop diuretics: § Acute reduction in congestion. o But will increase renin secretion --> cardiac remodelling. § Chronic use is associated with resistance and RAS activation. o Additional use of K+ sparing diuretics is used to try to stop the rebound activation of RAS. (e..g spironolactone)

Warfarin how long does it take to act?

takes 5-6 days to act; takes long time --> so can't be used for immediate action. targets via indirect action hence onset is slower.

Dihydropyridine calcium channel blockers cause arterial vasodilation. True/ False

true

What type of channel is muscarinic receptor?

type 2 - G-protein coupled

GAs - Mechanism of action: Neuroanatomy - Amnesia

via influences on GABAA a5 subunits: o Decrease synaptic transmission in the hippocampus and amygdala. § a5 GABAA subunits are at a high conc. here as opposed to the rest of the body

What are most drugs?

weak acids or weak bases. Therefore, drugs exist in ionised (polar) and non-ionised (non-polar) forms - the ratio depends on the pH

Legislation on over the counter sales of analgesics

§ 1998 pack size restricted paracetamol to 16x500mg tablets. § 2009 guidelines state: o No more than 2 packs per transaction. o Illegal to sell more than 100 pills per transaction. § Deaths have fallen by 43% since 2009. ** not all shops follow it though.

Molecular structures of barbiturates

§ 6 structure ring § Barbs tend to have a single ring structure with two R-groups. o R groups are - ethyl groups and phenyl/1-methylbutyl.

Potency of alcohol

§ Alcohol has a LOW potency (it is a very general molecule). o Influences a lot of receptors due to its uncomplicated shape however doesn't fit a lot of the receptors very well so not a lot of efficacy ** hence compared to nicotine and cocaine, need a lot more to get the same effect. *No pharmacological target for alcohol * Low affinity and efficacy for the target.

CYP450 System

§ Drug metabolism can be enhanced or inhibited by co-administration of other drugs. § CYP450 system has been most extensively studied. o Metabolism by a single isoenzyme - few examples. o Metabolism by multiple isoenzymes - most drugs. § Thus, co-administration of a CYP450 inhibitor may not affect metabolism rate as some isoenzymes can pick-up the slack for the inhibited isoenzyme.

GABA and krebs cycle

§ GABA via GABA-T --> Succinic Semialdehyde (SSA) via SSDH --> Succinic Acid (goes back into TCA cycle (GABA shunt)).

Phase 2; Conjugation with Glutathione

§ Glutathione is used to remove potentially toxic compounds. § Glutathione is the conjugating agent.

Proton pumps in stomach

§ H+-K+-ATPase (proton pump): •Expressed on secretory vesicles within parietal cells • increases [Ca2+]i --> increases cAMP --> translocation of secretory vesicles to parietal cell apical surface --> H+ secretion. o calcium and cAMP (Gs protein) can increase proton pump activity. § Ulcer formation: •Increased activity of proton pump - increased H+ secretion --> reduction gastric pH and increased acidity

Cytochrome P450 enzymes

§ Important enzymes in phase 1 reactions (involved in the metabolism of most drugs). § Predominantly found in the Liver. Found in smooth endoplasmic reticulum. § There are multiple ISOENZYMES involved in drug metabolism (up to 57 varieties). § There are certain drugs that can inhibit/induce the CYP450 enzyme system (i.e. smoking --> cancer!)

Alcohol Effects on lipid metabolism/platelet formation

§ In small doses - thrombosis formation risk of atherosclerosis/ischaemic heart disease § Cause - HDL cholesterol esterification, plaque formation, thromboxane A2 platelet aggregation.

Endothelial Dysfunction in Atherosclerosis

§ Increased endothelial permeability. § Upregulation of adhesion molecules (key in inflammation too) § Leucocyte adhesion (neutrophils and monocytes). § Migration of leucocytes into artery wall. •So firstly, the endothelium is not working properly. •The endothelium is an active line of cells, it makes growth factors and inflammatory mediators etc. •If the endothelium is not functioning properly, it is more likely that things will get through the endothelial laye

Second part of alcohol metabolism

§ Liver and GIT metabolism: o Acetaldehyde --> Acetic acid via: § Aldehyde dehydrogenase. · Polymorphisms can be found in this enzyme leading to Asian flush. § Disulfiram - inhibitor of aldehyde dehydrogenase. o Effective in alcohol aversion therapy as build-up of acetaldehyde makes you feel sick and not want to drink alcohol.

Opioids - nauses/vomiting pic network

§ Low-dose opioids active Mu receptors in the CTZ (Chemoreceptor Trigger Zone) and stimulate vomiting. o The Mu receptor stimulates disinhibition by switching OFF GABA secretion --> activate CTZ --> medullary vomiting centre. **CTZ - samples blood and detects noxious stimuli and cause vomiting; gut can cause vomiting and also balance and thoughts in head

What is the main risk factor for alzheimers?

§ Main risk factor - Age § Huge economic cost in the UK (more than cancer and heart disease) BUT low research investment. § Nov 2016 - ONS announces AD & dementia are leading cause of death in UK § Genetics - APP (amyloid precursor protein), PSEN, ApoE (hereditary ~ 8%). two types of alzheimer's - late onset with age-related or hereditary early-onset due to genetics (small proportion).

Pharmacological evidence supporting the monoamine hypothesis of depression

§ Monoamine theory of depression - depression is a functional DEFICIT of central MA transmission; Mania is a functional EXCESS of MA transmission. o mirrored by NA and 5-HT (serotonin) deficits/excesses. § There is good pharmacological evidence to support this theory but biological evidence is inconsistent. reserpine used to be used as anti-HT drug until depressive effects seen (prevents loading of NA and 5-HT into vesicles) § cocaine may seem to be argument against it because it decreases NA but no anti-depressant effect. o Biological evidence: § A reduction in NA metabolites is not concurrent with a worse depression. § Delayed onset of the clinical effect of drugs (a few weeks sometimes) - possibly due to adaptive changes in brain and not MA theory causing depression: o There is a downregulation of - a2, b and 5-HT receptors. **General conclusions still remain firm for MA theory of depression. § Some recent studies say depression could also be due to HPA axis and increased CRH (and thus cortisol) or hippocampal neurodegeneration.

Parkinson's disease clinical features: summarise the principle motor and non-motor clinical feature of the disease

§ Motor deficits - Bradykinesia, resting tremor, rigidity, postural instability. § Non-motor deficitis - Olfactory & autonomic dysfunction, sleep disorder

Alcohol chronic effects on Liver

§ NAD+: o You require NAD+ for a lot of functions and so alcohol dominates the use of NAD+ and thus NAD+ is not used for the other functions (not enough). o NAD+ in ETC, TCA cycle etc. o This leads to build up of other dangerous toxic by-product. o get fatty deposits, acidosis and ketosis. § Fatty liver - the lack of NAD+ means that TAGs are deposited in the liver.(after night out, but reversible if stop drinking for 24 hours). § Hepatitis - mixed function oxidases are upregulated in chronic alcoholics and these generate free radicals which then generate an inflammatory response. o MFO --> free radicals --> inflammation. o Cytokines are then released - e.g. increased IL-6 and TNF-a.(STILL REVERSIBLE, but if enough fibroblasts can lead to...) § Cirrhosis - fibroblasts lay down fibrin supportive structures that reduce regenerative capacity of liver - decreased regeneration and active liver tissue. Increased fibroblasts.Downstream, toxic levels build up in blood and need liver transplant. (Diversion of portal blood flow around fibrotic liver can cause oesophageal varices to develop which can bleed suddenly and catastrophically) **Cause - release of fatty acids from adipose tissue (due to sympathetic discharge). Impaired fatty acid oxidation (due to metabolic load imposed by alcohol). Contributory factor = Chronic malnutrition.

Drugs of Abuse Class 1: Narcotics

§ Narcotic (from the Greek word for 'stupor') -Drug that produces morphine like effects. e.g. Heroin § Effects on reward pathway: (opioid) receptors on GABAergic interneurons in the VTA i.e. disinhibit dopaminergic projection neurones

Ganglion blocking drug effects on the Body

§ Nicotinic receptor antagonists = Ganglion blocking drugs. § Fight & flight = SNS, rest & digest = PNS. § So depends upon situation as to what happens... o E.G. At rest after being given a GBD, you would expect to see an increased HR and bronchodilation. § CVS effects; hypotension - blood vessel vasoconstriction inhibited and kidney renin secretion inhibited (so no AngII). § Smooth muscle effects; pupil dilation, decreased GI-tone, bladder dysfunction, bronchodilation. § Exocrine secretions; decreased secretions. **-Sympathetically dominated: •Kidneys and vasculature --> Hypotensive effect -Paraympathetically dominated: a) Eyes à Pupil dilation b) Lungs --> Bronchodilation c) Exocrine --> Reduced secretions d) Bladder dysfunction and loss of GI motility

Parkinson's disease neuropathology: Identify the dopaminergic pathway in the brain which degenerates and how the loss of dopamine triggers the motor clinical symptoms; and explain which other neuronal pathways are affected in Parkinson's and what is the underlying pathological process

§ Nigrostriatal pathway - substantia nigra pars compacta (SNc) to the striatum. Inhibition results in movement disorders. § Severe loss of dopaminergic cells in SNc: Lewy bodies & neurites

Glaucoma classification

§ Normal IOP is about 15mmHg (10-20mmHg) and is maintained by the balance between the production of aqueous humour and the resistance to its return to the venous system. § Glaucoma occurs when a raised IOP damages the nerve fibres and results in progressive optic atrophy. § Glaucoma classification: a) Secondary - when IOP >20mmHg is found in the presence of an ocular disturbance which can reasonably be assumed to lead to a raised pressure (e.g. trauma). b) Primary - there are 3 types and it can be diagnosed when there is no evidence of ocular or general cause of secondary glaucoma.

Opiate receptors - Cellular Mechanism of Action

§ Opiate receptors cellular mechanism of action is via depressant actions. § There are 3 main depressant mechanisms: 1) Hyperpolarisation - increase potassium efflux (cell more diff to depolarise and hence decreased activity) 2) Reduce Ca2+ influx - for NT exocytosis 3) Reduce AC activity - for general cell activity. § Opioid effects: o Analgesia. o Euphoria. o Anti-tussive. o Respiratory depression - very dangerous. o Stimulation of CTZ (Chemoreceptor Trigger Zone) - nausea/vomiting. o Pupillary constriction and GI effects.

Opioid effects

§ Opioid effects: o Analgesia. o Euphoria. o Anti-tussive. o Respiratory depression (medulla) - very dangerous. o Stimulation of CTZ (Chemoreceptor Trigger Zone) - nausea/vomiting. o Pupillary constriction o GI effects.

Opioids - tolerance

§ Opioids upregulate levels of arrestin (protein inside cell) in the tissues. § Arrestin promotes receptor internalisation. § The over-internalisation of receptors means the tissue becomes less receptive to opioids and so becomes tissue tolerant.

Why do other NSAIDs not have same incidence of side effects compared to aspirin?

§ Other NSAIDs have the same side effects as aspirin (except for the prolonged bleeding time), but a lower incidence of these effects. This is because: a) They inhibit cyclo-oxygenase reversibly (e.g. ibuprofen, indomethacin) not irreversibly. b) Side effects can be reduced by topical application. c) Gastric ulceration can be minimised by co-administration of a proton pump inhibitor.

Mild to moderate versus severe behavioral and subjective effects of cocaine in humans.

§ Other effects: o Local anaesthetic effect - blocks sodium channels. o Cocaine causes vasoconstriction, decrease in cerebral blood flow and inflammation in the walls of the brain vessels (vasculitis). § Stimulants - See also methylenedioxymethamphetamine (ecstasy), caffeine

PGE2 activates which four receptors

§ PGE2: o Activates 4 receptors - EP1, EP2, EP3, EP4. o cAMP-dependant (EP2/4) OR Ca2+ mobilisation (EP1/3) OR both (EP3)! o Unwanted actions: § Increased pain perception. § Thermoregulation. § Acute inflammatory response. § Other - immune responses, tumorigenesis, inhibition of apoptosis (so more likely necrosis)

PGE2 analogues lower the pain threshold how?

§ Pain sensitisation - stimulation of PG receptors sensitises the nociceptors which causes pain acutely & chronically. •EP4 receptor antagonist blocks the effect of the PGE2 analogue. o Co-injection of COX2 inhibitors prevents or reduces duration of prolonged pain. o Mechanism - unclear: § is cAMP mediated, ePac pathway activated, greater activation of P2X3 nociceptive receptors (hence is block the production of PGE2 can combat this hyperalgesia). § Activation of EP1 and EP4 receptors (in spine & periphery). § Endocannabinoid involvement (neuromodulators in thalamus, spine and periphery) · This is not mutually exclusive - i.e. cross-talk between prostanoids and endocannabinoids. § NSAIDS increase beta-endorphin in spine.

Is paracetamol an NSAID?

§ Paracetamol is a good analgesic for mild-to-moderate pain and also has antipyretic activity. § However, it is NOT a NSAID because it has no anti-inflammatory activity. § Its actions appear to be largely restricted to nervous tissue. Its mechanism of action is unclear. § Paracetamol is generally a very safe drug, but in overdose it may cause irreversible LIVER FAILURE, because high levels of one of its minor metabolites are produced. § This metabolite is normally safely conjugated with GLUTATHIONE, but if excess paracetamol is taken, glutathione levels are depleted and the metabolite oxidises thiol groups of hepatic enzymes causing cell death and fatal organ failure. § If not promptly treated with ACETYLCYSTEINE (or occasionally oral methionine), death may occur some days after the patient has taken the initial overdose. § Legal restrictions on sales of paracetamolhave significantly reduced the number of fatalities from overdose in the UK.

How do you think that cocaine pharmacokinetics contribute to the addictive potential of the drug

§ Pharmacokinetics leading to addictive capabilities: o Fast onset of action and short half-life due to plasma and liver cholinesterases. o Lots of methods to take the drug. o hence crack cocaine said to be most addictive.

Prostanoid receptors are named based on what?

§ Prostanoids (5 known) bind to 10 known receptors. o DP1-2, EP1-4, FP, IP1-2, TP - named based on potency. o All g-protein coupled (have effects independent of coupling however). o Knock out mice show that prostanoid effects are extremely complex o Physiological and pro-inflammatory o Too much to cover so we focus on effects of PGE2 to 4 receptors.

GAs clinical setting for analgesia, muscle relaxaion and amnesia

§ Relief of pain (analgesia)-Opioid (e.g. i.v. fentanyl) § Muscle relaxation - Neuromuscular blocking drugs (e.g. suxamethonium § Amnesia - Benzodiazepines (e.g. i.v. midazolam

Why thiazides versus other diuretics for hypertension?

§ Response: o Initial (4-6 weeks) - reduction of BP due to reduction of blood volume. o After 4-6 weeks - plasma volume restored due to tolerance. hence diuretic effect decreases with time. o Chronic thiazides however also cause reduction of TPR (vasodilation) due to - activation of eNOS, Ca2+-channel antagonism and opening of KCa-channels. Leads to... § NO production, less calcium influx and hyperpolarisation.

STEMI

§ STEMI - ST-Elevated MI. § Caused by - white thrombus - fully occluded coronary artery. o Damage to endothelium. o Atheroma formation. o Platelet aggregation. § Management: o Reduce lipid formation, platelet aggregation/activation and dissolve thrombus - antiplatelets and thrombolytics: § APs - Clopidogrel, aspirin, Abciximab. § TLs - Alteplase.

Kidney Physiology- Proximal Convoluted Tubule

§ Sodium is taken up and co-transports the H2O. o 65-70% of Na+ reabsorbed. § There are lots of basal Na+/K+-ATPases to retain the sodium gradient. § Oncotic pressure is assisted by the movement of proteins and sodium. § Carbonic anhydrase on inside the lumen ensures that bicarbonate is broken down to allow CO2 and H2O to pass into the cell. § Many drugs (exogenous agents) are exported out of the PCT into the lumen via transporters into urine. o Na/H exchange, sodium is coupled with glucose and AAs (hence aids absorption) o bicarbonate is good buffer; carbonic anhydrase converts HCO3- to CO2 and h20 and then inside cell carbonic anhydrase converts back to HCO3- and H+. *(H+ used again for Na/H exchange; and bicarb absorbed into blood with sodium).

Epidural and spinal anaesthesia

§ Spinal anaesthesia - intrathecal (sub-arachnoid space injection into CSF): Hip replacement: o Injection close to spinal ROOTS - e.g. lower limb, abdominal, pelvic surgery. o requires Low dose. o Reduces BP and so can cause prolonged headache (hence need to monitor BP). o Glucose can be added to increase specific gravity of injection so the LA doesn't travel up the CSF to the brain and can control where in spine want the effect. § Epidural anaesthesia - injection into fatty tissue of epidural space: o Injection close to spinal ROOTS - e.g. lower limb surgery (like spinal anaesthesia), painless childbirth. o Cons - slower onset and higher doses required (hence may get systemic toxicity) o Pros - more restricted action, less effect on BP.

How can spinal cord module pain transmission?

§ Spinal cord can modulate pain tolerance. o Pink arrows = descending inhibition from NRM. § Some go directly into decreasing pain transmission in the spinothalamic tract. § Some project into the SG (Substantia Gelatinosa): o Can modulate/determine level of inhibition necessary on the sensory neurones from the NRM.

The following three patients have all received treatment for heart failure. A 72-year-old woman presented to hospital with acute heart failure and was administered spironolactone. A 63-year-old hypertensive man is treated with bendrofluazide daily to treat mild chronic heart failure. A 79-year-old woman was treated with furosemide to treat acute pulmonary oedema associated with chronic heart failure. In general terms, what type of target to these drugs act on?

§ Spironolactone is a mineralocorticoid receptor antagonist i.e. it's drug target is a receptor.Bendrofluazide and furosemide are thiazide and loop diuretics respectively. Both act on transport proteins. Thiazides block the Na+/Cl- co-transporter in the distal convoluted tubule. Loop diuretics block the Na+/K+/2Cl- co-transporter in the ascending limb of the loop of Henle.

The vulnerable atherosclerotic plaque

§ Stable plaque - thick fibrous cap (mostly of collagen) - protects lumen from lipid core adacent to it. o Sometimes have a thinner lumen but are less likely to rupture. narrow lumen and thick wall. § Unstable plaque - thin fibrous cap, rich core of lipids & macrophages, less evidence of VSMC proliferation. •Plaque rupture is associated with greater influx and activation of macrophages, accompanied by the release of matrix metalloproteinases that are involved in the breakdown of collagen. •The narrowing in the left image is more significant so this could produce symptoms due to reduced coronary blood flow. •The image on the left also has a thinner fibrous cap, so it is vulnerable to rupture

Phase 2; Acetylation

§ The acetyl group is transferred to an electron rich atom. §Acetyl-CoA is the conjugating agent.

Cannabis, resin and hash oil

§ The cannabis is the plant, the hashish/resin is the trichomes (glandular hairs that contain the highest concentration of THC) and the hash oil is the solvent extract. § Cannabis contains over 400 compounds with >60 being cannabinoids. o Delta9-THC (deDelta9-Tetrahydrocannabinol) is the most potent cannabinoid. o Positive aspects of smoking weed are from cannabidiol - experts believe a balance between these two (cannabidiol vs. delta9-THC) is needed.

The patient's neck flexion is confirmed to be torticollis. This has arisen due to reduced dopaminergic activity in the central nervous system (CNS). Following this episode his haloperidol is changed to an alternative antipsychotic. § Consider the table below, which provides information on the binding affinity of several anti-psychotic agents for different receptor sub-types. What antipsychotic would you recommend?

§ The extra-pyramidal side effects are mediated via dopamine receptors so you would want to switch to a drug with a mechanism of action that doesn't target dopamine receptors. Clozapine and Quetiapine are the obvious choices here. § You might ask the students if they would choose one over the other and why. Some of them might suggest that clozapine has more evidence of reducing the negative symptoms of schizophrenia. § You may ask why we don't just start with the atypicals? Both are associated with significant weight gain. Clozapine also required careful monitoring for agranulocytosis. § NB - Second generation anti-psychotics have not been shown to have a significant effect on negative symptoms. It is common for schizophrenia patients to be treated with SSRIs to treat the negative symptoms.

Influenza treatment

§ The influenza viruses consist of influenza A, B & C, which have a multipartite genome of linear single-stranded RNA divided into 7-8 segments. The envelope is embedded with numerous glycoproteins and is particularly rich in hemagglutinin and neuraminidase. **Virology •Multipartite single stranded RNA virus •Envelope protein neuraminidase --> required for release **Tropism •Nose, throat & bronchi • The virus is highly contagious and is transmitted through the air or via numerous bodily secretions. It generally appears in seasonal epidemics resulting in numerous deaths although it is not fatal in the vast majority of individuals. Once infected the virus binds to and replicates within epithelial cells of the throat and lungs. The clinical manifestations of influenza virus infection includefever, cough, myalgia and general malaise. **Treatment • The most effective treatment for vulnerable individuals is a vaccine but for post-exposure prophylaxis in individuals who are not sufficiently protected by the vaccine the neuraminidase inhibitors oseltamivir and zanamivir are recommended. •Neuraminidase inhibitor --> Oseltamivir (Tamiflu) and Zanamivir. Issue is have to take it within 48h of development of symptoms.

§ A 20-year-old male visits his GP with persistent apprehensive feelings about upcoming events. He reports that for the last 3-months he cannot concentrate on his work because he is worried about failing his upcoming exams and he has been having difficulty sleeping for the last 4 weeks. The GP conducts a series of tests and subsequently refers the patient to a psychoeducational group. In a follow-up appointment the GP diagnoses the patient with generalized anxiety disorder (GAD). Despite the UK guidelines for GAD management the GP prescribes a benzodiazepine. § In the following six months the patient's mental status deteriorates and he is diagnosed with depression. After being tapered off diazepam he was prescribed fluoxetine and then venlafaxine, which stabilised his condition. ** Differentiate between fluoxetine and venlafaxine. Why might fluoxetine be the first line anti-depressant in this case?

§ The major difference between the two is that fluoxetine is specific for the serotonin transporter, whereas venlafaxine has variable effects on other monoamine transporters - at low dose it is more specific for serotonin transporters, at higher doses it can block the noradrenaline transporter. It also has mild effects on dopamine transporters. § There is no consensus on which anti-depressant is most efficacious - it is a little bit patient specific. However, NICE would advocate fluoxetine as first line treatment for the following reasons.; § As the more selective drug, the side effect profile is expected to be lower (a better risk-benefit ratio). § It is also the most cost-effective solution (i.e. cheapest). § It is common to combine anti-depressants if the single drug does not produce a significant reduction in symptoms (the doctor would have to be very careful that the patient had been adherent). In terms of combining drugs, be sure that the two drugs are safe when used together and be aware of increased side effect burden. **A bit of extra info on side-effects (for interest) § generally in depressed patients the risk of suicide is greatest around the time of their presentation to medical services, however the risk of suicide may increase in the early stages of treatment for depressive illness. § a modest increase in the risk of suicidal thoughts and self-harm for SSRIs compared with placebo cannot be ruled out. § there is insufficient evidence of any marked difference in suicidal risk between the different SSRIs, or between SSRIs and other antidepressants

§An 18-year-old male presents to his GP and states that he has been feeling increasingly paranoid over the last few months. He is finding it increasingly difficult to motivate himself and feels incredibly 'flat'. He admits that he started 'vaping' two years ago and regularly uses cannabis. He also admits that he recently tried cocaine, which improved his mood. He is subsequently diagnosed with schizophrenia following a neuropsychological examination, referred to a cognitive behavioural therapy (CBT) clinic and prescribed the antipsychotic drug haloperidol, 5 mg QD. § On a particularly difficult day the gentleman takes double the recommended dose and attends A&E because his upper body is stiff and neck is rotated to the left and locked in flexion. **Name the type of side-effect that the patient is experiencing.

§ The patient is experiencing an extrapyramidal side-effect (EPS), which are relatively common with the FGA haloperidol. The specific effect is known as torticollis and is a type of dystonia.NB: students only need to know that it is an EPS, not the specifics. Background: Haloperidol is primarily a dopamine D2-receptor antagonist and falls into the category of drugs known as first-generation antipsychotics (FGAs) or aka typical neuroleptics.NB: QD means once daily

Remnant lipids and the endothelium

§ The remnant lipids are the chylomicron remnants that are very good at infiltrating the endothelial wall. § Remnants include: o VLDL. o Chylomicron remnants. o IDL. § Note - remnants are MORE important than LDLs here ****The INFLAMMATORY part of atherosclerosis is NOT caused by LDL, but by lipid remnants!***

nAChR

§ There are 5 subunits in the receptor; a1, a2, b, d, g. o two alpha subunits are there which 2 molecules of Ach binds to - when binds, channel open get big influx of sodium ions and getting end plate receptors. § There is a large extracellular domain and a slightly smaller intracellular domain. § The density of these receptors on the motor-end plate is VERY high

Other Sedatives/Hypnotics

§ Zopiclone - a "Z-drug", short acting (t1/2 = 5 hrs) and acts on BDZ receptors (but they are NOT BDZs - they are cyclopyrrolones). o Similar efficiacy to BDZs. o Have minimal hangover effects but dependency is still a problem.

Lithium in treatment of depression

§ acts to control mania as well as depression; mainly used prophylactically in bipolar depression. § long plasma half-life and narrow therapeutic window. hence, S/Es are common § main S/Es: nausea, thirst, polyuria, hypothyroidism, tremor, weakness, mental confusion, teratogenesis. Acute overdose --> confusion, convulsions and cardiac dysrhythmias. § action enhanced by diuretic drugs § alternative mood-stabilising drugs include carbamazepine, valproate.

Glucocorticoids and IBD

Ø Examples: Prednisolone, Fluticasone, budesonide (not absorbed - hence fewer S/E) Ø Powerful anti-inflammatory and immunosuppressive drugs Ø Derived from the hormone cortisol Ø Activate intracellular Glucocorticoid Receptors which can then act as positive or negative transcription factors. o Very potent anti-inflammatory and immunosuppressive actions of GCs. o When given systemically, chronic glucocorticoid administration causes many unwanted effects e.g. osteoporosis, kidney damage, electrolyte imbalance etc. o Prednisolone S/E greater than Budesonide (topical) BUT standard oral glucocorticoids better than budesonide at inducing remission in active CD. **in pic - downregulates IL-1B and TNF-a (also downregulated by aminosalicylates). also downregulating actions of macrophages and T cells,

Summary of ADRs

Ø much of therapeutics is about avoiding or detecting ADRs. Ø most are avoidable. Ø drug interactions are an important added risk for ADRs. Ø more drugs = more trouble.

Heparin

• activates AT-III (decreases fIIa & fXa)

Identify the main classes of anti-emetic drugs. Outline their principle clinical uses and mechanism of action

•5-HT3A receptor antagonists: chemotherapy induced N&V •Histamine H1 receptor antagonists: motion sickness •Muscarinic receptor antagonists: motion sickness •Dopamine D2 receptor antagonists: gastroparesis induced N&V

Enterohepatic recycling

•A drug or its metabolite is reabsorbed in the gut after biliary excretion and taken to the liver via the hepatic portal vein. -This means the drug will persist for longer (can lead to problems with toxicity) - drug persistence

Diagnosis of Epilepsy

•Brain activity can be measured using: a) Electroencephalography (EEG) - to see seizure activity b) Magnetic resonance imaging (MRI) - used to see if underlying brain damage/ cause rather than to see seizure

Dalteparin

•Low-molecular weight heparin - activate AT-III (decreases fXa)

Low-molecular weight heparins

•Low-molecular weight heparins (LMWHs, e.g. Dalteparin) - activate AT-III (decreases fXa)

are drugs mostly strong acids/bases or weak?

•Most drugs are either weak acids or weak bases. Therefore drugs exist in ionised (polar) and non-ionised (non-polar) forms - the ratio depends on the pH •E.g. A drug with a pKa of 3.5 is a weak acid and a drug with a pKa of 8.9 is a weak base

Development of newer NSAIDS

1) Dual COX and LOX inhibitors: • For asthmatic patients (stop release of leukotrienes too) •No safe option on the market (liver injury) 2) Nitric oxide or Hydrogen sulphide releasing NSAIDS: •NO and H2S protective to GI and CVS •A number of options undergoing testing •Late stage clinical trials

Increased parasympathetic activity in the cardiovascular system decreases the risk of cardiac arrhythmias. True/ False

True

Increased parasympathetic activity in the cardiovascular system is reversed by atropine. True/ False

True

Inflammation in atherosclerosis may be associated with modified LDL particles. True or False?

True

Morphine causes pupil constriction. True or false?

True

Neuroleptic drugs are used to treat schizophrenia. True/ False

True

Neuroleptic drugs produce extensive side effects due to their antagonism at other receptors. True/ False

True

Opioid drugs are drugs of abuse. True/ False

True

Opioid drugs can cause respiratory depression. True/ False

True

Opioid drugs include methadone. True/ False?

True

Protease inhibitors enhance the activity of warfarin. True/ False

True

Regarding ethanol metabolism: Asian races possess genetic variations in the enzyme alcohol dehydrogenase. True/ False

True

Haloperidol is not effective at treating which symptom of schizophrenia?

affective flattening (negative symptom)

What do you give in paracetamol overdose?

n-acetylcysteine

Example of amino acid conjugation Phase 2 metabolism

two reactions possible: - with carboxylic acid group of AA - with amino group of AA

Types of antibiotic resistance?

1) Destruction Enzymes 2) Additional target 3) Alteration of target 4) Alteration in drug permeation 5) Hyperproduction

What would be observed after blockade of nicotinic acetylcholine receptors in an individual at rest?

- loss of parasympathetic function (at rest) : constipation, bronchodilation, decreased sweat production, decreased urinary frequency, long-sightedness

Effect of tubocurarine on NM transmission

- at bottom have skeletal muscle fibre - electrodes at endplate and away from endplate - stimulate motor axon to get release of Ach at end plate. top panel shows normal response. get AP and then AP towards end - after tubocurarine - get release of Ach, but as nAChR blocked, get little blip and no propagation and hence no contraction

How does liver excrete drug?

- biliary excretion (large Mr molecules can concentrate) - active transport systems - into bile (bile acids and glucuronides) - for water-soluble molecules

How do ACEi treat hypertension and HF?

* ACE Inhibitors (ACEi): Often have '-ipril' endings. BP = TPR x CO 1) Hypertension: a) Reduce TPR - more bradykinin & less AngII --> reduces TPR via less AT1R-mediated vasoconstriction so less BP and more bradykinin vasodilation. b) Sodium retention - less Na+ retention in the kidneys via blocked actions of AngII on the AT1R in the kidneys AND less aldosterone secretion as blocked AT1R in the adrenal medulla. c) Thirst drive - less SNS activation of thirst in the brain via AT1R. 2) Heart Failure: a) Reduce TPR - less vasoconstriction via AT1R in the peripheral vasculature so less TPR so less afterload on the heart so ionotropic effects of the heart decrease. b) Reduce preload - venodilation (bradykinin?) means less preload, so less cardiac work and less stress on heart.

Adrenaline: Clinical uses

* Cardiogenic Shock - o This can happen when you have a heart attack/MI or cardiac arrest. o This action mainly happens via the beta 1 receptor - positive inotropic action * Spinal Anaesthesia: o As you are anaesthetising through the spine, you take away the sympathetic output to the peripheral resistance vessels. o This means that you get relaxation of peripheral resistance vessels so the patient wont be able to maintain their blood pressure. o If you give a little bit of adrenaline at the same time you can constrict the blood vessels so you can maintain the blood pressure. * Local Anaesthesia: o There is a little bit of adrenaline mixed in with the local anaesthetic because the adrenaline causes constriction of the blood vessels in the local area thus preventing the clearance of the anaesthetic from the area. o If the anaesthetic was given without adrenaline then it will wear off faster. o This is due to alpha-1 mediated vasoconstriction.

Pharmacokinetics of suxamethonium

* MOA: - causes extended end plate depolarisation --> 'DEPOLARISATION BLOCK' (PHASE 1). essentially overstimulating the NMJ. - FASCICULATIONS (muscle twitching) --> FLACCID PARALYSIS due to muscle relaxation * Pharmacokinetics: - Route of administration (ROA) = I.V. (HIGHLY CHARGED) - DURATION OF PARALYSIS ~ 5 MIN (SHORT) - METABOLISED BY PSEUDO-CHOLINESTERASE IN LIVER & PLASMA * USES: •endotracheal intubation •MUSCLE RELAXANT FOR ECT (electroconvulsive therapy) so don't damage themselves. last resort in treatment for depression. *UNWANTED EFFECTS: 1) POST-OPERATIVE MUSCLE PAINS 2) BRADYCARDIA: Ø DIRECT MUSCARINIC ACTION ON HEART (ATROPINE) - not usually an issue as atropine is included in pre-medication which blocks suxamethonium 3) HYPERKALAEMIA : - if reduce innervation to skeletal muscle fibre because of soft tissue injury/ burns then may reduce cholinergic input to skeletal muscle fibres and response is upregulation of NaChR on surface of fibre on endplate and beyond = denervation supersensitivity. if give suxamethonium going to get amplified response due to increased no. of nAChR and hence going to get big sodium influx but also potassium efflux --> hyperkalaemia. ØSOFT TISSUE INJURY OR BURNS --> VENTRICULAR ARRHYTHMIAS / CARDIAC ARREST [AVOID!]. hence use non- depolarising blocker instead. 4) increased INTRA-OCULAR PRESSURE - because of contraction of extraocular muscles ØAVOID FOR EYE INJURIES, GLAUCOMA. hence use non-depolarising blockers

Suxamethonium mechanism of action (nAChR agonist)

* MOA: - causes extended end plate depolarisation --> 'DEPOLARISATION BLOCK' (PHASE 1). essentially overstimulating the NMJ. - FASCICULATIONS (muscle twitching) --> FLACCID PARALYSIS due to muscle relaxation * Pharmacokinetics: - Route of administration (ROA) = I.V. (HIGHLY CHARGED) - DURATION OF PARALYSIS ~ 5 MIN (SHORT) - METABOLISED BY PSEUDO-CHOLINESTERASE IN LIVER & PLASMA * USES: •endotracheal intubation •MUSCLE RELAXANT FOR ECT (electroconvulsive therapy) so don't damage themselves. last resort in treatment for depression. *UNWANTED EFFECTS: 1) POST-OPERATIVE MUSCLE PAINS 2) BRADYCARDIA: Ø DIRECT MUSCARINIC ACTION ON HEART (ATROPINE) - not usually an issue as atropine is included in pre-medication which blocks suxamethonium 3) HYPERKALAEMIA : - if reduce innervation to skeletal muscle fibre because of soft tissue injury/ burns then may reduce cholinergic input to skeletal muscle fibres and response is upregulation of NaChR on surface of fibre on endplate and beyond = denervation supersensitivity. if give suxamethonium going to get amplified response due to increased no. of nAChR and hence going to get big sodium influx but also potassium efflux --> hyperkalaemia. ØSOFT TISSUE INJURY OR BURNS --> VENTRICULAR ARRHYTHMIAS / CARDIAC ARREST [AVOID!]. hence use non- depolarising blocker instead. 4) increased INTRA-OCULAR PRESSURE - because of contraction of extraocular muscles ØAVOID FOR EYE INJURIES, GLAUCOMA. hence use non-depolarising blockers

Antibiotic classes: identify the main classes of antibiotic drugs and distinguish between them in terms of mechanism of action

**Intracellular targets: 1.Nucleic acids - Sulphonamides (DHOp), Trimethoprim (DHFR) 2.DNA gyrase - Fluoroquinolones e.g. Ciprofloxacin 3.RNA polymerase - Rifampicin 4.Bacterial ribosomes - Macrolides (Aminoglycosides, Tetracyclines) **Cell membrane targets: 1.Peptidoglycan (PtG) synthesis - Vancomycin inhibits pentapeptide 2.PtG incorporation - Carbapenems, Cephalosporins & Penicillins inhibit transpeptidase 3.Membrane stability - Lipopeptides & Polymyxins

Unwanted effects of suxamethonium

* MOA: - causes extended end plate depolarisation --> 'DEPOLARISATION BLOCK' (PHASE 1). essentially overstimulating the NMJ. - FASCICULATIONS (muscle twitching) --> FLACCID PARALYSIS due to muscle relaxation * Pharmacokinetics: - Route of administration (ROA) = I.V. (HIGHLY CHARGED) - DURATION OF PARALYSIS ~ 5 MIN (SHORT) - METABOLISED BY PSEUDO-CHOLINESTERASE IN LIVER & PLASMA * USES: •endotracheal intubation •MUSCLE RELAXANT FOR ECT (electroconvulsive therapy) so don't damage themselves. last resort in treatment for depression. UNWANTED EFFECTS 1) POST-OPERATIVE MUSCLE PAINS 2) BRADYCARDIA: Ø DIRECT MUSCARINIC ACTION ON HEART (ATROPINE) - not usually an issue as atropine is included in pre-medication which blocks suxamethonium 3) HYPERKALAEMIA : - if reduce innervation to skeletal muscle fibre because of soft tissue injury/ burns then may reduce cholinergic input to skeletal muscle fibres and response is upregulation of NaChR on surface of fibre on endplate and beyond = denervation supersensitivity. if give suxamethonium going to get amplified response due to increased no. of nAChR and hence going to get big sodium influx but also potassium efflux --> hyperkalaemia. ØSOFT TISSUE INJURY OR BURNS --> VENTRICULAR ARRHYTHMIAS / CARDIAC ARREST [AVOID!]. hence use non- depolarising blocker instead. 4) increased INTRA-OCULAR PRESSURE - because of contraction of extraocular muscles ØAVOID FOR EYE INJURIES, GLAUCOMA. hence use non-depolarising blockers

Uses of Suxamethonium mechanism of action (nAChR agonist)

* MOA: - causes extended end plate depolarisation --> 'DEPOLARISATION BLOCK' (PHASE 1). essentially overstimulating the NMJ. - FASCICULATIONS (muscle twitching) --> FLACCID PARALYSIS due to muscle relaxation * Pharmacokinetics: - Route of administration (ROA) = I.V. (HIGHLY CHARGED) - DURATION OF PARALYSIS ~ 5 MIN (SHORT) - METABOLISED BY PSEUDO-CHOLINESTERASE IN LIVER & PLASMA * USES: •endotracheal intubation •MUSCLE RELAXANT FOR ECT (electroconvulsive therapy) so don't damage themselves. last resort in treatment for depression. UNWANTED EFFECTS 1) POST-OPERATIVE MUSCLE PAINS 2) BRADYCARDIA: Ø DIRECT MUSCARINIC ACTION ON HEART (ATROPINE) - not usually an issue as atropine is included in pre-medication which blocks suxamethonium 3) HYPERKALAEMIA : - if reduce innervation to skeletal muscle fibre because of soft tissue injury/ burns then may reduce cholinergic input to skeletal muscle fibres and response is upregulation of NaChR on surface of fibre on endplate and beyond = denervation supersensitivity. if give suxamethonium going to get amplified response due to increased no. of nAChR and hence going to get big sodium influx but also potassium efflux --> hyperkalaemia. ØSOFT TISSUE INJURY OR BURNS --> VENTRICULAR ARRHYTHMIAS / CARDIAC ARREST [AVOID!]. hence use non- depolarising blocker instead. 4) increased INTRA-OCULAR PRESSURE - because of contraction of extraocular muscles ØAVOID FOR EYE INJURIES, GLAUCOMA. hence use non-depolarising blockers

Adrenoreceptor subtypes

* a1- Vasoconstriction, Relaxation of GIT. * a2 - Inhibition of transmitter release, contraction of vascular smooth muscle, CNS actions (so acc diminish sympathetic activity) * b1- Increased cardiac rate and force, relaxation of GIT, renin release from kidney (imp. in hypertension) * b2- Bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis * b3- Lipolysis

Clonidine

* alpha 2 agonist. a2>>a1>>>b1/2. * get negative feedback, binds to a2 prejunctional receptor, get PARAsympathetic response as it mediates the release of NE. **overall: § a2>>a1>>>b1/b2. § Mainly acts on the prejunctional neuronal a2-receptor to inhibit NA release. § Clinical uses include: a) Treatment of hypertension and migraine. b) Reduces sympathetic tone. § a2-mediated presynaptic inhibition of NA release. § Central brainstem action within baroreceptor pathway to reduce sympathetic outflow.

Opioids - miosis

* important because is a clinical sign - if someone unconscious comes into A and E and have constricted pupils --> opioid overdose. § Most overdoses exhibit dilated pupils (mydriasis) as the decreased brain function reduces the level of constriction but opiates cause "pin-prick" eyes. Opioids switch on the parasympathetic nerve. § Activation of the Mu receptors causes a dis-inhibitory effect by decreasing GABA secretion and thus stimulates the pupil constriction in the Edinger-Westphal nucleus.

Hyperkalaemia and renal failure as S/E of ACEi and ARBs

** Hyperkalaemia - ACEi, ARB - care with K+ supplements or K+-sparing diuretics. as sodium not being transported in with water, potassium not excreted out. o Aldosterone promotes K+ loss so aldosterone inhibitors (ACEi, ARBs) produce a hyperkalaemia. o Renal failure (in patients with renal artery stenosis) - ACEi, ARBs. o Glomerular filtration is maintained by AngII so you need to be careful in renal failure patients.

Unwanted effects of LAs

** Lidocaine: 1) CNS - if too high dose - paradoxical effects considering a LA (probably due to loss of GABA inhibition): § Stimulation. § Restlessness, confusion. § Tremor. 2) CVS - due to Na+-channel blockade: § Myocardial depression. § Vasodilation. § Reduction in BP. ** Cocaine - SNS actions: 1) CNS: § Euphoria, excitation - due to blocking effects in re-uptake of NA. 2) CVS: § Increased CO. § Vasoconstriction. § Increased BP. **Note the stark difference in CVS symptoms between the two LAs.

Diagnosis and treatment of NSAID caused peptic ulcer

** Presentation •Epigastric pain, burning sensation **Investigations & Diagnosis •Carbon-urea breath test - negative •Stool antigen test - negative •NSAID use - positive. e.g. regular use of aspirin --> ulcers. **Pathophysiology NSAID: •Directly cytotoxic •Reduces mucus production •Increases likelihood of bleeding •Increased acidity --> peptic ulcer **Treatment: •Removal of NSAID (this might be tough if someone taking it for heart problems, so this is dependant on what the NSAID is being used for) •Proton Pump Inhibitor or histamine H2 receptor antagonist (Ranitidine) - 4-8 weeks •H2 receptor increases acid secretion

Causes of antibiotic resistance

** Threat •'CATASTROPHIC', 'APOCALYPTIC', 'AS BIG A RISK AS TERRORISM' UK Chief Medical Officer. •~ 70% of bacteria developed resistance. •25000 yearly death rate - Europe & US. **Causes: 1) Unnecessary prescription: •~ 50% of antibiotic prescriptions not required. Occurs mostly in primary healthcare (GPs) 2) Livestock farming: •~ 30% of UK antibiotic use in livestock farming. Worst in USA. 3) Lack of regulation: •OTC availability in Russia, China, India 4) Lack of development: •Very few antibiotics in recent years

Directly acting cholinomimetic drugs

- are typical AGONISTS at muscarinic receptors 1) choline ester (bethanechol: M3- selective) 2) alkaloids (pilocarpine: non-selective)

Metoclopramide

**MOA: 1) Dopamine D2 receptor antagonist (primary action) on CTZ: a) Prokinetic - stimulates gastric emptying b) Inhibits D2 receptors in CTZ 2) 5-HT3A receptor antagonist: Inhibits activation of CTZ. **USE: Used to treat nausea and vomiting associated with: o uraemia (severe renal failure) o radiation sickness o gastrointestinal disorders o cancer chemotherapy (high doses) e.g.. Cisplatin (intractable vomiting) **UNWANTED EFFECTS: § In CNS: drowsiness, dizziness, anxiety. extrapyramidal reactions; children more susceptible than adults (Parkinsonian-like syndrome: rigidity, tremor, motor restlessness). **NOTE: In the endocrine system: hyperprolactinaemia, galactorrhoea, disorders of menstruation. **PHARMACOKINETIC CONSIDERATIONS may be administered orally; rapidly absorbed; extensive first pass metabolism, may also be given i.v., crosses BBB, crosses placenta.

Glutamatergic Synapse and pharmacology

**Neurotransmission: 1.VGSC --> depolarisation --> VGKC --> repolarisation 2.Ca2+ influx through VGCCs --> vesicle exocytosis 3.SVA2 allows vesicle attachment to membrane 4.Glutamate activates excitatory post-synaptic receptor **Pharmacology: 1.VGSC antagonist: e.g Carbamazepine 2.VGCC antagonist: Ethosuximide (T-type antagonist); 3.SV2A inhibitor: Levetiracetam 4.Glutamate receptor antagonist: Topiramate

ADR Frequency by Drug Use

**Note that ADR frequency increases with increased individual drug use. more medications you take, the more ADRs.

Diazepam

**Pharmacodynamics: •GABA receptor, PAM --> increases GABA-mediated inhibition **Pharmacokinetics •Rectal gel - Fast-onset (within 15 min); half-life (2 hours). If given orally, has longer duration of action. **Indications: •Status epilepticus

Sodium valproate

**Pharmacodynamics: •Inhibits GABA transaminase --> increases GABA-mediated inhibition. Also get less glutamate produced from breakdown of GABA --> less excitation too. ** Pharmacokinetics: •Fast onset (1h); half-life (12h) **Indications: •Indicated for ALL forms of epilepsy. Hence is go-to drug if see someone come in epilepsy.

Symptoms of schizophrenia

**Positive symptoms: o increased Mesolimbic dopaminergic activity --> o Hallucinations: Auditory & visual o Delusions: Paranoia o Thought disorder: Denial about oneself **Negative symptoms: o decreased Mesocortical dopaminergic activity o Affective flattening: lack of emotion o Alogia: lack of speech o Avolition/ apathy: loss of motivation

Motion sickness

**Presentation: Motion sickness **Pathophysiology: § Labyrinth in ear canal - neural mismatch between what you are seeing and what you are feeling--> activates histamine receptors (H1) on vestibular nuclei (located in CNS that have afferent inputs to CNS) § Vestibular nuclei activate muscarinic receptors (M1-M5) on CTZ. § CTZ activates VC (via M1-M5 again), which causes nausea. **Treatment: § Promethazine - H1 receptor antagonist on vestibular nuclei. § Hyoscine (scopolomine) - non-selective muscarinic receptor antagonist. Reserved for more serious cases of motion sickness. Is a centrally acting, non-selective muscarinic receptor antagonist. Muscarinic receptors located on both CTZ and VC.

Chemotherapy induced nausea and vomiting

**Presentation: § Chemotherapy (Cisplatin) for lung cancer § Chemotherapy induced nausea & vomiting (CINV) **Pathophysiology: § Cisplatin is toxic to enterochromaffin cells (ECs) in gastric antrum- release of free radicals § Free radicals --> excessive 5-HT release § 5-HT - activates 5-HT3A receptors (ligand-gated ion channel that responds to 5-HT (serotonin) ligand) on nerve fibres to chemoreceptor trigger zone (CTZ); is located outside BBB even though is located in midbrain of CNS. § CTZ activates nerves fibres to vomiting centre (VC) § VC --> nausea. Vomiting centre has many different types of receptors (m1-5) that are activated by many different substances. Vomiting centre is also known as area of postrema. **Treatment (triple therapy): § Ondansetron - 5-HT3A receptor antagonist § Glucocorticoids - reduce free radical production. anti-inflammatory - so reduces inflammation caused by chemotherpies. § Aprepitant - neurokinin-1 receptor antagonist. are mainly expressed in vomiting centre; are activated by substance P which is released by higher centre of brain (primarily involved in pain perception, nausea and vomiting). ** reason for triple therapy in CINV: get biphasic response - get immediate nausea and later stage. Ondansetron is effective for immediate stage. Glucocorticoids and Aprepitant are more effective for treating later stage CINV.

Gastroparesis and nausea and vomiting

**Presentation: § Vomiting, due to unknown cause. Abdominal pain & bloating. History of type 2 diabetes **Pathophysiology § Gastroparesis - delayed emptying of the stomach § Reduced stomach contraction § results in 5-HT - activates 5-HT3A receptors on CTZ. Dopamine D2 receptor is also on CTZ; is not directly activated by serotonin but high levels of dopamine acting on D2 receptor can result in nausea and vomiting. § CTZ activates nerves fibres to vomiting centre (VC) § VC --> nausea **Treatment of N&V: Metoclopramide (dual mechanism of action): 1) Dopamine D2 receptor antagonist (primary action) a) Prokinetic - stimulates gastric emptying b) Inhibits D2 receptors in CTZ 2) 5-HT3A receptor antagonist: Inhibits activation of CTZ

DVT and pulmonary embolism treatment

**Subsequent Presentation: •Chest pain •Dyspnoea & Tachypnoea **T-wells score increased, o2 sats decreased, use CTPA **now change in treatment is HEPARIN as well in addition to dalteparin initially. but other than that treatment stays basically same.

Herpes Simplex Virus treatment

**Virology: •Double-stranded DNA •Surrounded by tegument & enclosed in a lipid bilayer **Tropism: •Herpes Simplex Virus (HSV)-1 --> cold-sores •HSV-2 --> genital herpes **Treatment: •NucleoSide analogues --> Aciclovir. Is phosphorylated three times and blocks replication of viral DNA. Can be taken either everyday if lots of genital herpes; or take high dose over 5 days.

A man and a woman of similar height and weight share a bottle of wine. Explain why the blood alcohol levels in the woman are likely to be higher

**Women: o Body water: 50% Men: o Body water: 59% **Men have more ADH, more body water. § Men have a greater volume of body water (and women have more adipose tissue) which allows alcohol to be more widely distributed in men so at a lower concentration (more diluted). § Men have more ADH as well so more ability to metabolise

Diseases associated with thrombosis

**cell-based model of coagulation.: 1. INITIAION: o This step is localised to the cells that express tissue factor (TF), which are normally found outside the vasculature. The initiation phase involves the small scale production of thrombin mediated by tissue factor bearing cells. 2. Amplification o The coagulation process only proceeds to the amplification phase when the TF- bearing cells come into contact (i) platelets which are only present within blood vessels and (ii) the factor VIII/ vonWillebrand factor (vWF) complex, which is only released when the vascular endothelium is damaged. The amplification phase sets the stage for subsequent large-scale thrombin production andinvolves thrombin-mediated activation of factors V, VIII, IX on the surface of platelets. 3. Propagation o The phase predominantly occurs on the surface of the platelets that have been recruited to the site of injury. It involves large scale production of thrombin on the surface of activated platelets resulting in the formation of fibrin strands, which are key constituents of a blood clot. ** The drugs used in the treatment of thrombosis can also be broadly categorised into three sections, which correlate reasonably well with the three stages of the cell-based theory of coagulation. 1) The drugs that directly or indirectly target the clotting factors are known as ANTICOAGULANTS and these will affect all three stages of coagulation 2) The ANTIPLATELET drugs affect processes involved in platelet aggregation and these drugs will only act on stages 2 & 3 of the cell-based theory of coagulation 3) The THROMBOLTIC (or fibrinolytic) drugs are able to dissolve the fibrin strands holding the clot together and these drugs will only affect the final stage of coagulation.

How do opioids act as an anti-tussive?

**production of cough: stimulation of mechano/chemoreceptors (Ach/NK C-fibres)--> impulses to medulla via vagus (5HT1A receptors)--> parasympathetic and motor nerves to cause contraction of diaphragm, abs and intercostal muscles. Opioids cause 3 effects to supress coughing (centrally and peripherally): 1) Central: a) 5HT1A-receptor antagonist: § 5HT1A-receptor is a negative feedback receptor for serotonin and firing leads to suppression of serotonin and activation of the cough reflex. § Inhibition of this receptor increases serotonin so less cough. b) Medulla direct depression (stops medulla signalling back down efferent pathway to cause muscle contraction) 2) Peripheral: a) ACh and NK (Neurokinin) release inhibition so less transmission down the sensory nerves to the vagus afferents.

Nicotine - pharmacodynamics - CV

**v similar to cocaine effects on CV but also has a negative impact on lipid profile (increases VLDL and LDL). § Cardiovascular: o Stimulation of the nAChRs leads to a SNS activation (CNS & adrenals): a) Increased - HR, SV. b) Vasoconstriction of skin arterioles. c) Vasodilation of coronary arterioles, skeletal muscle arterioles. o Increased lipolysis, FFAs, VLDLs, decreased HDL. o Increased TXA2, reduced NO. § Long-term use --> Cardiovascular disease.

white vs red thrombi

**white vs red thrombus: o red thrombi e.g. in DVT (vein) tend to be RBC rich and better treated with anticoagulants (LMWH and warfarins). o white thrombus: forms in artery. tend not to form inside actual blood vessel wall, high content of foam cells (macrophages ingested into thrombus and take on lots of cholesterol --> white appearance). treated with antiplatelets and thrombolytics. *overall: 1) vein vs artery 2) RBC rich vs foam cell rich 3) anticoagulant vs antiplatelet 4) lumen vs inside blood vessel wall

What type of disease is IBD?

*autoimmune diseases. o defective interactions between the mucosal immune system and the gut flora. there are 10x more gut bacteria than host cells. o This leads to disrupted innate immunity --> uncontrolled inflammation --> physical damage.

New targets for IBD

*other inflammatory mediators: ØIntegrins (needed for cells to migrate) ØInterleukins (IL12; IL17;IL23) ØInterleukin receptors ØJanus kinase (JAK) cytoplasmic cell signalling **might get same issue with anti-TNFa though where we develop antibodies to the antibodies.

Braak staging

*parkinsons: § Stages 1 & 2 - Synuclein deposition in the DM, RN and LC - pre-symptomatic. § Stages 3 - Synuclein deposition in SN - onset of motor deficits. § Stage 4, 5, 6 - deposition in the amygdala and cortical areas. § There needs to be decline of at least 80-85% DA neurones and 70% of the striatal DA before symptoms can appear. o This is due to the compensatory mechanisms of the body which prevent the appearance of clinical symptompa

Release of ACh from synaptic knob

- AP arrives - Merging of synaptic vesicles with synaptic knob membrane triggered by binding of Ca2+ - Exocytosis of ACh into synaptic cleft - About 300 vesicles per nerve signal - binds to Ach receptor - Acetylcholinesterase breaks down into choline and acetate - choline has specific transporter back into presynaptic cell **§ Muscarinic effects can be replicated by muscarine and can be abolished by LOW doses of the antagonist atropine. § After atropine blockade of muscarinic receptors, larger doses of ACh can induce effects similar to those caused by nicotine. § Remember nicotine receptors exist on all post-ganglionic neuronal cell bodies (and ACh acts on all of them throughout the ANS) - look to final sheet for reference. § Cholinomimetics = ACh mimicking drug

Angiotensin receptor blockers For hypertension

- ARB (Angiotensin Receptor Blockers) E.G. Losartan. § Prevent binding of AngII to AT1 receptors, preventing the renal and vascular actions of Ang II. § Uses - hypertension and HF

Calcium channel blockers to treat HT

- Calcium-Channel Blockers: E.G. Amlodipine, Verapamil. § Smooth muscle contraction: 1) Membrane depolarisation opens VGCC. 2) Ca2+ enters and binds calmodulin (CaM). 3) Ca2+-CaM complex activates MLCK. 4) MLCK mediated phosphorylation --> VSM contraction. § CCBs - DHP selective for blood vessels, Non-DHP for heart + vessels: 1) Dihydropyridines (DHPs) - non-rate limiting: § Amlodipine - no negative ionotropic effect. § Prophylactic treatment of angina. 2) Non-DHPs - rate-limiting: § Verapamil - negative ionotropic effect.

History of alcohol

- China 9000 B.C fermentation pot - Egyptians had breweries 6000 years ago, credit god Osiris with introducing wine to humans - Babylon -1750BC -Ancient Greeks used large quantities of wine and credited god Baccus with introducing drink. - Dionysus in Roman time

How do drugs get into systemic circulation after administration? (pharmacokinetics: absorption)

- Drug molecules move around the body in two ways: a) Bulk flow transfer i.e. in the bloodstream b) Diffusional Transfer i.e. molecule by molecule over short distances. drugs have to traverse both aqueous and lipid environment - hence need to be both lipophilic and hydrophilic: i) Compartments = Aqueous e.g. Blood, lymph, extra-cellular fluid, intra-cellular fluid ii) Barriers = Lipid i.e. cell membranes (epithelium/endothelium)

How many subunits in a nicotinic receptors?

- FAST Ligand gated ion channels •5 subunits: α β γ δ ε •Subunit combination determines ligand binding properties of the receptor N.b: •Muscle type at NMJ: 2α ,β, δ, ε. •Ganglion type in ANS: 2α, 3β (CNS - similar) (shown in diagram) § The subunit combination determines the ligand-binding properties of the receptor. •Effects of ACh relatively weak on these recetpros, i.e. need high ACh to stimulate

Drug target site type 1: receptors

- Proteins WITHIN cell membranes (usually), or can be intracellular - Activated by NT or hormone - Defined by agonists & antagonists - 4 types of receptors (defined by structure and transduction system e.g. GPCR, ion-channel, kinase-linked, intracellular steroid) - Examples of drugs: acetylcholine (agonist) atropine (antagonist)

Drug target site type 2: ion channels

- Selective pores - allow transfer of ions down electrochemical gradients - 2 types: 1) voltage-sensitive e.g. VSCC 2) receptor-linked e.g. nAChR o Examples of drugs :Local Anaesthetics (LAs) - reduce further influx of sodium channels - reduces AP generation reaching sensory cortex, Calcium channel blockers (end in -dipine) - used in CV pharmacology, anti-hypertensive, arrhythmias, angina

What is the importance of drug metabolism?

- The biological half-life of the chemical is decreased. - The duration of exposure is reduced. - Accumulation of the compound in the body is avoided. - Potency/duration of the biological activity of the chemical can be altered. - The pharmacology/ toxicology of the drug can be governed by its metabolism.

Drug target site type 3: transport systems

- Transport against concentration gradients (glucose, ions, NTs) - Specificity for certain species e.g. NA terminals specific for NA - Examples :Na+/K+-ATPase , NA 'uptake 1' - Examples of drugs : a) Tricyclic anti- depressants (TCAs) - slow down NA uptake - so get enhancement of NA action b) Cardiac glycosides - stimulate heart in HF e.g. digoxin - increased sodium intracellular ==> increased calcium influx --> increased contraction

What does drug metabolism do generally?

- We design relatively lipid soluble drugs. - Body alters the drug to make it less lipid soluble and easier to excrete. - The process of metabolism involves the conversion of drugs (usually quite lipid soluble) to metabolites (usually less lipid soluble and easier to excrete).

Clonidine uses

- a2 agonist ØTreatment of hypertension and migraine ØReduces sympathetic tone -a2 adrenoceptor mediated presynaptic inhibition of NA release -Central action in brainstem within baroreceptor pathway to reduce sympathetic outflow.

Mertazapine

- a2 receptor antagonist - inhibits negative inhibition of NA release. o Increases NA and 5-HT release. o Other R interactions (sedative) o Useful in SSRI intolerant patients.

Angina different types and treatment

- almost always due to atherosclerosis. 1) Stable-pain on exertion. Increased demand on the heart and is due to fixed narrowing of the coronary vessels e.g. atheroma. 2) Unstable-pain with less and less exertion, culminating with pain at rest. Platelet-fibrin thrombus associated with a ruptured atheromatous plaque, but without complete occlusion of the vessel. Risk of infarction. 3) Variable-occurs at rest, caused by coronary artery spasm, associated with atheromatous disease. - to treat can other increase oxygen supply or stop heart working so hard so it requires less o2. this second option is what beta blockers do (but that also means can't exercise as effectively.

NTs for somatic nervous system

- alpha motor neurones - sits in vertebral column with cell body in ventral horn - motor neurone has single axon and is cholinergic - sciatic nerve is longest motor neurone in body

Methyldopa method of action

- an antihypertensive medication. § Methyldopa is taken up by noradrenergic neurons --> methyldopa is the decarboxylated and hydroxylated to form a false NT, a-methyl-noradrenaline. § Methyldopa is then not broken down within the neuron by MAO --> tends to accumulate in larger quantities than NA and displaces NA from vesicles. § Method of action: a) Less active than NA on a1-receptors - less effective in causing vasoconstriction. b) More active on presynaptic a2-receptors - more negative feedback on NE release. c) Some minor effects on CNS - stimulates vasopressor centre *§ Benefits: o Renal and CNS blood flow well maintained so used in patients with renal insufficiency or CNS disease. o Recommended in hypertensive pregnant women as no adverse effects on foetus (but DOES cross placenta). *§ Adverse effects: o Dry mouth, sedation, orthostatic hypotension, male sexual dysfunction.

How does Kidney excrete drug?

- blood delivered to kidney, 20% filtered and 80% in plasma - low Mr are filtered at glomerulus, but most stay in blood - active secretion of drug occurs into tubule (by transporters) - if drug is lipid-soluble (depending on pH and pKa) enough it may get passively reabsorbed back into blood - so may need to make more water-soluble to increase excretion

Factor 4/4 influencing drug distribution : localisation in tissues

- can get stuck in a tissue, tends to be in adipose tissue - don't usually worry as has little blood supply (2% cardiac output), if have very fat-soluble drugs (e.g. anaesthetics), even though only small amounts are passing through adipose tissues - a lot of drug is housed in tissue which will slowly leak back into blood. hence even after GA still after 24 hours can get super drowsy

Venlafaxine

- dose-dependent re-uptake inhibitor - 5-HT>NA>DA. (at low dose inhibits 5-HT only, as increase dose it inhibits NA uptake too, then increased dose inhibits DA uptake too. o 2nd line for severe depression. o SNRI.

What do nicotinic receptor antagonists cause hypotension?

- heart - increases cardiac output - BVs - dilatation - kidney - decreased renin secretion

Muscarinic effects on heart

- here are M2 inhibitory receptors - high density in atria and SA and AV node - when stimulate receptors then get less cAMP --> decreased CO and HR (negative inotropic effect (reduced force of contraction) and chronotropic effect) *Overall*: § The depressing effect on the heart (GI muscarinic receptors) is mediated by: 1. Reduction of cAMP. 2. Decreased Ca2+ entry. § Decreased CO. 3. Increased K+ efflux. § Decreased HR

Where would want sympathomimetic drugs to act for glaucoma?

- if activate b1 receptor, is coupled to aqueous humour production; so don't want b1 agoinst - a2 receptor - interferes with b1 function by blocking NA production decreases humour production - a1 receptor - causes vasoconstriction. is best. increased BP causes fluid to force out of eye

Does the measurement of bioavailability always reflect the effectiveness of a drug?

- if topical cream/ointment not as relevant or if site of action is in the GIT itself - if prodrug - will get metabolised into active drug - is important particularly for orally administered drugs - liver metabolism ('first pass metabolism'). - The liver is the MAJOR organ of drug metabolism - the "Hepatic First Pass" metabolism can be extensive. ** In the case of oral administration of a medicine, several factors may influence bioavailability: 1. the physicochemical characteristics of the drug (ionisation in gut) 2. gastrointestinal pH 3. whether or not the drug is passively or actively transported 4. gastrointestinal motility 5. particle size of the drug 6. physicochemical interaction between drug and gut contents (e.g. chemical interaction between calcium and tetracycline antibiotics)

Example of absorption of aspirin

- ingest --> bulk flow to stomach and SI --> lipid barrier to get into blood --> flows into blood to tissues --> capillary wall --> ECF --> tissue capillary wall --> target cell

Explain why disulfiram can be effective as alcohol aversion therapy

- inhibitor of aldehyde dehydrogenase. o Effective in alcohol aversion therapy as build-up of acetaldehyde makes you feel sick and not want to drink alcohol. o High levels of acetaldehyde --> flushing, tachycardia, hyperventilation, panic/distress

Draw a diagram to show the autonomic influences on blood pressure and indicate where pindolol may have its actions.

- kidney - renin release - blood vessels - vasoconstriction - heart o antagonists: high affinity, no efficacy o hypertension: block beta receptors on kidneys, so less renin --> less ATII and less aldosterone --> less Na+ and water reabsorption o tachycardia - block beta 1 receptors on heart --> lowers HR o arrhythmia - could be due to problem with AVN, hence using drug to block b1 receptor here could work; but could also potentially look at calcium channel blocker

What are the two major routes of drug excretion?

- mainly KIDNEY and also LIVER (in bile, higher Mr) Methods: 1) Kidneys - renal excretion: Ultimately responsible for the elimination of most drugs glomerulus - drug-protein complexes not filtered o proximal tubule - active secretion of acids and bases. o proximal and distal tubules - lipid soluble drugs reabsorbed (passive diffusion). 2) Liver - biliary excretion: o Some drugs are concentrated in the bile (usually larger molecular weight conjugates). o active transport (systems for bile acids and endogenous glucuronides). 3) ENTEROHEPATIC CYCLING: o once excreted into the gut (via bile) the drug (or metabolite) may be reabsorbed. o a drug trapped in a cycling process persists in the body for longer than expected 4. Lungs - excreted via expired air: o passive diffusion of volatile compounds. 5. Other routes (usually of little quantitative importance) gastrointestinal secretions, saliva, sweat, milk, genital secretions, integument.

Factor 3/4 influencing drug distribution : capillary permeability (tissue alterations - renal, hepatic, brain/CNS, placental)

- most capillaries are continuous; if lipid soluble then can easily diffuse. if have water-soluble drugs then have to have a mechanism to get across membrane - BBB has tight junctions - hence need to take into account when want drug to access brain - also have fenestrated or discontinuous capillaries

Where does most phase 1 metabolism occur?

- most occurs in liver - cytochrome P450 enzymes in SER in hepatocytes - 57 enzyme subtypes - different subtypes metabolise different drugs - most common phase 1 metabolism is oxidation (often start with hydroxylation though)

Target biomarker profile for the clinical management of paracetamol overdose

- paracetamol is a widely uesd analgesic and anti-pyretic drug. it is taken orally, absorbed and distributed throughout the body enabling pain and fever relief. It is largely metabolised in the liver which results in excretion of paracetamol as non-toxic metabolited. it can cause lliver damage after over-dosage. Phase 1 metabolism of paracetamol is mediated by CYP450s and results in the formation of a reactive intermediate, NAPQI.

Why do alpha 2 receptors and baroreceptors reduce the effectiveness of phentolamine?

- phentolamine blocks alpha 1 and 2 receptors. by blocking a2, reduce negative feedback, more NA released into synapse and more to bind to a1 instead of phentolamine and get more competition and a1 activity than with just a1 receptor blocking drug. - if alpha blockers block blood vessels --> dilates them. BR respond to this, if BP high, BR firing high and high PNS to vagus. if BR falls, then less vagal stimulus and more sympathetic NS which increase HR and stroke volume. so body's system compensates for pharmacological action - prazosin in theory should have no effect on a2 receptor, but both reduce BR firing and get compensatory increase in CO.

Where do all neuromuscular blocking drugs act?

- postsynaptically 1) non-depolarisng (competitive antagonists) e.g. tubocurarine, atracurium 2) depolarisng (agonists) - cause depolarising block e.g. suxamethonium. This is so good at stimulating due to its VERY similar structure to ACh. N.b. - a) THEY DO NOT AFFECT CONSCIOUSNESS b) THEY DO NOT AFFECT PAIN SENSATION c) Respiration must ALWAYS be assisted when taking these drug (UNTIL DRUG INACTIVE OR ANTAGONISED)

Bioavailability can be influenced by the biology of the human gut. The drug can be metabolised to inactive products by...

- the microbes within the gut lumen - enzymes present in the gut wall - enzymes in the liver

Structures of NMJ blocking agents

- tubocurarine antagonist has quarternary ammonium like Ach - hence tubocurarine can bind to nAChR but no efficacy. more rigid structure with little free rotation - succinylcholine split into half - is two Ach - hence is good agonist for nAChR. more free rotation around bonds

Type 4 of drug antagonism: Pharmacokinetic antagonism

- § Drugs (agonists) that are administered, are antagonised by the body itself that reduces the concentration of the active drug at the site of action. i. I.E. reduced absorption, blocked distribution, increased metabolism, increased excretion. - Antagonist --> decreases concn of active drug at site of action ¯ by less absorption, increased metabolism, increased excretion e.g. barbiturates Þ Clinically important interaction

Muscarinic effects on vasculature

- •Most blood vessels do NOT have parasympathetic innervation •ACh acts on vascular endothelial cells to stimulate NO release via M3 AChR •NO then induces vascular smooth muscle relaxation •Result is a decrease in TPR o thus decreased BP (decreased HR, CO and vasodilation) - This is more relevant to the clinical use of cholinomimetics than normal physiology

Salbutamol (ventolin) summary

-It is a synthetic catecholamine derivative with relative resistance to MAO and COMT and therefore has a much longer duration of action than adrenaline or noradrenaline. **Clinical Uses 1) Treatment of Asthma - β2-relaxation of bronchial smooth muscle - inhibition of release of brochoconstrictor substances from mast cells. 2) Treatment of threatened premature labour -β2-mediated relaxation of uterine smooth muscle ØSIDE EFFECTS- Reflex tachycardia, Tremor, blood sugar dysregulation ØCAUTION must also be taken with cardiac patients, patients with hyperthyroidism and diabetics (β2-receptors stimulate glycogenolysis)

phentolamine

-Nonselective α-blocker (a1 and a2 antagonist) -Give to patients on MAO inhibitors who eat tyramine containing foods -Toxicity: orthostatic hypotension, reflex tachycardia

Angina

-Tight chest pain -Oxygen supply to myocardium is insufficient -Oxygen supply and demand mismatch: § Pain spreads down dermatome T1 in the chest, arm and neck and is bought on by exertion of excitement. § Types of angina: a) Stable - pain on exertion - due to fixed narrowing of coronary vessels. b) Unstable - pain with less exertion and with pain at rest - thrombus but without complete occlusion of vessel. c) Variable - occurs at rest, caused by coronary artery spasm, associated with atheromatous disease. § b-adrenoceptor antagonists reduce myocardial demand by: a) decrease ionotropic effect. b) decrease chronotropic effect (and at low doses do not affect bronchial smooth muscle. c) decrease systolic BP, reduce oxygen demand whilst maintaining effort. § b-adrenoceptor antagonist's adverse effects include: fatigue, insomnia, dizziness, sexual dysfunction, bronchospasm, bradycardia, heart block, hypotension - thus not used in patients that these are exacerbated in. o I.E. not used in congestive heart failure patients.

Molecular structures of benzodiazepines

-epam, -epate. § Usually a triple-ring structure. e.g. diazepam § flumazenil is BZ antagonist (similar structure)

Barbiturates

-tone, -tol, -tal. •RANGE OF CLINICAL USES INCLUDING: SEDATIVE / HYPNOTIC e.g. AMOBARBITAL Ø used for SEVERE INTRACTABLE INSOMNIA Ø t½ = 20-25h *UNWANTED EFFECTS (NOT drugs of 1st choice - usually replaced by benzodiazepines due to lower S/E). § These drugs have many unwanted effects so are not a 1st line: o Small therapeutic windows - depress respiration and overdosing is lethal. o Reduce REM sleep --> "hangovers"/irritabiltiy. o Induce enzymes. o Potentiate effects of other CNS depressants - alcohol. o Tolerance and dependence become issues --> withdrawal syndrome (insomnia, anxiety, tremor, convulsions, death)

How would you demonstrate statistically in a larger survey that b-blockade had occurred?

. Take a mean of the data on a large group of subjects which you then compare to a placebo to highlight obvious effects.

NMJ transmission

1) Acetyl Coa + choline --> Ach (by CAT enzyme) 2) AP 3) Ca2+ influx 4) exocytosis of Ach into cleft 5) diffuses across onto post synaptic membrane (skeletal muscle fibre) - NAChR (type 1 ion channel linked). influx of ion in skeletal fibre (end plate potential - is graded potential depending on Ach and receptor conc) --> AP (all or nothing) 6) receptor shuts; Ach broken down into acetate and choline by acetylcholinesterase. 7) This is then taken up inside terminal and used again to make more Ach. - nAChR here at NMJ are different to the nAChR in the ganglions. means we can have drug antagonists that have slight selectivity for NMJ. 5 subunits to nAChR - two alpha subunits are there which 2 molecules of Ach binds to ** § NM transmission - production of ACh using CAT --> AP propagation --> Ca2+ influx --> ACh exocytosis --> ACh binds to receptors and Na+ influx --> ACh esterase breaks down ACh --> recycling by uptake. § 3 most important NM-blocking drugs are: 1) Competitive - tubocurarine, atracurium. 2 Depolarising - suxamethonium. § The NMJ nAChR is different in structure to the ganglionic (ANS) nAChR and so we can produce selective drugs just for the somatic nervous system.

Two classes of K+ SPARING DRUGS

1) Aldosterone receptor antagonists e.g. spironolactone 2) Inhibitors of aldosterone-sensitive Na+ channels e.g. amiloride

Adrenoceptor antagonists - SUMMARY

1) Alpha 1, β1 and β2 blocker - Carvedilol 2) Beta blockers: oNon selective: Propranolol, Pindolol oBeta 1 selective: Atenolol, Nebivolol (NO release), Sotalol (inhibits K+ channels) 3) Alpha blockers: oNon-selective - phentolamine oAlpha 1 selective - prazosin 4) False transmitter - Methyldopa *Clinical uses: Hypertension, Arrhythmias, Angina and Glaucoma

Side effects of neuroleptics

1) Anti-emetic effect: o Block DA-R in CTZ - Phenothiazone - effective at treating chemotherapy induced emesis. o Many neuroleptics also good at blocking histamine receptors so also treats motion sickness. 2) Extrapyramidal side effects: o Block DA-R in nigro-striatal system à induces Parkinson's patients-like side effects. § Acute dystonia - involuntary movements. § Tardive dyskinesias - involuntary movements - made worse by drug withdrawal or anti-cholinergics. · Must treat dyskinesias by giving MORE drug! 3) Endocrine effects: o Tubulo-infundibular involvement so acts in inhibit prolactin secretion via D2-receptors so anti-psychotics INCREASE prolactin secretion. 4) Blocking alpha-adrenoceptors: o Orthostatic hypotension. 5) Blocking 5-HT: o Weight gain. 6) Blockade of cholinergic muscarinic receptors: o Peripheral anti-muscarinic side effects - SNS effects - blurring vision, dry mouth, constipation, sedation.

Other anxiolytic drugs

1) Antidepressants: o SSRIs - effective but have a delayed response (a week) but are very popular. o used for long-term treatment. o less sedation and dependance. o also as depression and anxiety often occur together - can target both with this. 2) Antiepileptic's: o Valproate, Tiagabine. o both enhance GABA transmission in brain. 3) Antipsychotic's: o atypical antipsychotics: Olanzapine, Quetiapine - useful but have marked SEs. 4) Propranolol - improves the physical symptoms of anxiety: tachycardia (Beta-1 adrenoreceptors) and tremor on skeletal muscle (beta-2 adrenoreceptors). o Acts on SNS. o damps down stage fright too - used by actors, dancers, snooker players. 5) Buspirone - 5HT1A-Receptor agonist with fewer side effects (less sedation) but has a slow onset of action (days/weeks).

A 73-year-old takes daily aspirin to treat rheumatoid arthritis. At the time that he started taking aspirin, his GP also prescribed misoprostol. 1) Why is aspirin effective in the treatment of rheumatoid arthritis? 2) Why did the GP prescribe misoprostol? 3) What effects does misoprostol have on rheumatoid arthritis - consider the receptor selectivity of misoprostol?

1) Aspirin blocks the formation of the prostaglandin PGE2 which has complex effects on immune pathways but is believed to act on EP4 receptors on both dendritic cells and on naive T-cells to increase the production and proliferation of Th17 cells. These cells produce IL-17 which is known to have destructive effects on bone and cartilage. Thus aspirin is effective due to the fact that it inhibits cyclooxygenase an d prevents the production of PGE2. 2) PGE2 stimulates mucus and bicarbonate secretion as well as downregulating HCl secretion. NSAIDS such as aspirin block this effect and can thus lead to the development of gastric ulcers. Misoprostol is a prostaglandin analogue that can replace the prostaglandins blocked by the actions of aspirin and thus bind to prostaglandin receptors to induce the protective effects described above. 3) In theory, the administration of a prostaglandin analogue should worsen the arthritis. Misoprostol has some receptor selectivity, and binds preferably to EP2 and EP3 receptors. It is believed that the protective effects in the stomach are mediated by EP3 receptors. Therefore, misoprostol should activate EP3 receptors in the stomach to promote the production of mucus/bicarbonate but have little effect on EP4 receptors and the negative effects in arthritis.

Clinical uses of muscarinic receptor antagonists atropine and hyoscine

1) Atropine: a) Normal dose - Little effect b) Toxic dose - Mild restlessness®Agitation (Less M1 selective) 2) Hyoscine; a) Normal dose - Sedation, amnesia b) Toxic dose - CNS depression or paradoxical CNS excitation (associated with pain) could have differing responses due to different selectivities for muscarinic subtypes e.g. M1 (Greater permeation into CNS. Influence at therapeutic dose).

What are the three main theories for AD?

1) Beta-amyloid (Ab): •b-secretase --> b-amyloid plaques 2) Tau aggregation: •Hyperphosphorylated tau --> neuronal instability 3) Inflammation: • activity of microglial cells

Alcohol acute effects

1) CNS - depressant mainly, complicated. 2) Euphoria - inhibit GABA release 3) CVS - cutaneous vasodilation flushing and increased HR (causes a warm feeling but heat loss); caused by central depression of sympathetic outflow (Direct vasodilation). 4) Endocrine - diuresis

Alcohol chronic effects

1) CNS: dementia, ataxia and wernicke-korsakoff 2) Liver: fatty liver, hepatitis, cirrhosis: Fat accumulation (fatty liver), Liver inflammation (hepatitis), Irreversible hepatic necrosis/fibrosis (cirrhosis). 3) GIT: carcinogenic 4) Endocrine - cushing's, male gynaecomastia

Voltage-gated Na+ channel blockers in treatment of epilepsy

1) Carbamazepine: a) Pharmacodynamics § Stabilises inactive state of Na+ channel --> reducing neuronal activity and less excitation of presynaptic glutamatergic terminal. b) Pharmacokinetics § Enzyme inducer § Onset of activity within 1 hour (fastish) § 16-30 hour half-life - hence doesn't need to administer often. c) Indications § Tonic-clonic seizures; partial seizures **NB: potential severe side-effects (SJS & TEN - Stevens-Johnson syndrome and toxic epidermal necrolitis ) in individuals with HLA-B*1502 allele. Often seen in chinese background. 2) Lamotrigine: safer during pregnancy. a) Pharmacodynamics § Inactivates Na+ channels --> reducing glutamate neuronal activity b) Pharmacokinetics § Onset of activity within 1 hour § 24-34 hour half-life c) Indications § Tonic-clonic seizures; absence seizures

Beta blocker - side effects

1) Cardiac failure worsening (CO reduction by blocking b2 and increased vascular resistance by blocking b2). 2) Bradycardia - b1 : Heart block - decreased conduction through AV node. **To alleviate these problems: 1) Non-selective beta blockers: •'Equal' affinity for b1 & b2 receptors •With intrinsic sympathetic activity e.g. Pindolol will have some beta 2 stimulating effects due to ISA or carvedilol with alpha 1 blocking effects can decrease TPR and alleviate this problem when doing daily tasks. 2) Mixed b- a blockers: •a1 blockade gives additional vasodilator properties •E.g. Carvedilol **ADDITIONAL S/E: 1) Bronchoconstriction - b2. 2) Hypoglycaemia (watch in diabetics on insulin) - b2 glycogenolysis/gluconeogenesis - masks hypoglycaemia. - HENCE BE WARY FOR ASTHMATICS AND DIABETICS. 3) Cold extremities and peripheral artery disease worsening - Loss of β2 receptor mediated cutaneous vasodilation in extremities. 4) (fatigue, impotence, depression and CNS effects (e.g. nightmares) - RCTs question validity of this).

First generation antipsychotics used in treatment of Schizophrenia

1) Chlorpromazine: o Discovered whilst developing new antihistamines o Primary mechanism of action - possibly D2 receptor antagonism. § Side effects: o High incidence - anti-cholinergic (affects histamine and dopamine receptors), especially sedation o Low incidence - extrapyramidal side-effects (EPS). 2) Haloperidol: o Very potent D2 antagonist (~ 50x more potent than chlorpromazine) o Therapeutic effects develop over 6-8 weeks o Little impact on negative symptoms §Side effects: •High incidence - ExtraPyramidalSide effects (EPS) - motor symptoms

A lady subsequently develops dementia alongside her Parkinson's disease. Knowing that the treatment options for dementia with PD are the same as Alzheimer's disease, outline the treatment options available and differentiate between them.

1) Cholinesterase inhibitors: these increase the extracellular levels of ACh and include: a) Donepezil: reversible acetylcholinesterase inhibitor b) Rivastigmine: an acetylcholinesterase and butyrlcholinesterase enzyme inhibitor c) Galantamine: acetylcholinesterase inhibitor that also activates nicotinic acetylcholine receptors 2) NMDA receptor antagonist: Memantine: antagonizes the NMDA receptor and is only licensed for moderate-severe Alzheimer's disease

Clinical Manifestations of Atherosclerosis

1) Coronary heart disease: Angina pectoris, myocardial infarction, sudden cardiac death 2) Cerebrovascular disease: Transient ischaemic attacks, stroke 3) Peripheral vascular disease: Intermittent claudication, gangrene

History of general anaesthesia

1) Crawford Long (1842) - first person to do surgery with anasthesia (using ether) 2) Horace Wells (20th Jan, 1845) - dentist. attempted public demo of GA. used nitrous oxide. 3) William Morton & Charles Jackson (16th Oct, 1846) - ether, successful public demo of tumour removal

Treatment for DVT vs NSTEMI vs Stroke

1) DVT & PE: •Presentation: swollen leg •Investigations: 2-level Wells score a) Thrombosis - initial stages •TF presentation •Prothrombinase-mediated formation of factor IIa (thrombin) b) Anticoagulants: •Parenteral: dalteparin (activate antithrombin) •Oral: rivaroxaban (FXa inhibitor) / warfarin (VKA) c) Risk factors: •Virchow's triad: rate of blood flow, consistency of blood, blood vessel wall integrity 2) NSTEMI: •Presentation: chest pain, SOB •Investigations: ECG, troponin a) Thrombosis - amplification •Thrombin (fIIa)--mediated platelet activation •ADP --> P2Y12 receptor --> COX & GPIIb/IIa b) Antiplatelets: •Aspirin: COX-1 inhibitor •Clopidogrel: ADP receptor (P2Y12) antagonist 3) STROKE: •Presentation: headache, dizziness & numbness in the face, arms and legs •Investigations: CT scan a) Thrombosis - propagation •Thrombin-mediated conversion of fibrinogen --> fibrin strands b) Thrombolytics: •Alteplase: tissue plasminogen activator

CNS Effects of long-term consumption of alcohol

1) Dementia (ventricular enlargement), degeneration of cerebellum (and other brain regions), peripheral neuropathy and myopathy. § Cause - Direct effects of ethanol or its metabolites such as acetaldehyde or fatty acid esters. Also, Thiamine deficiency due to malnutrition.

A 22-year-old woman who has spent the summer engaged in spraying fruit crops with pesticides is admitted to A&E with organophosphate (anticholinesterase) poisoning. 1) What is the most likely route of administration associated with the organosphosphate poisoning? 2) Explain why this patient might present with diarrhoea.

1) Either via inhalation and access to the pulmonary circulation through the alveoli or across the skin (trans-dermal) - in this case the drug needs to be very lipophilic to cross the skin in sufficient quantities. In both cases, the drug crosses the relevant barrier (Alveoli or skin) and enter the capillaries associated with that tissue. From the capillaries drugs diffuse into the venous system (pulmonary venous system in the lung) and return to the heart after which the drug will enter the systemic circulation. 2) Organophosphate poisoning would result in a blockade of cholinesterase in the synapse. This blockade would reduce the breakdown of acetylcholine in the synapse. The build up of acetylcholine would lead to a significant increase in muscarinic receptor activation - the more agonist is present, the more agonist receptor complexes will be formed per unit time, and the more powerful the tissue response will be. In the case of the gastro-intestinal tract, the muscarinic receptors increase gut motility, and this would speed up transit time through the gastro-intestinal tract which could be associated with diarrhoea.

Mechanisms regulating contractility in heart

1) Electrical excitation of the cell from action potentials arising from the sino-atrial node induce membrane depolarization. 2) This promotes gating of Ca2+ channels, which open and cause a small release of Ca2+ into the cytoplasm. 3) The small Ca2+ current induces a release of Ca2+ from the SR by a process called Ca-induced Ca-release. The release occurs through Ca2+ release channels commonly referred to as ryanodine receptors (RyR2). o Depolarization-induced influx of Ca2+ current (ICa) through the L-type channels contributes approximately 20-25% of the free Ca2+ in a cardiac twitch. o The release of Ca2+ through the RyRs contributes the remaining 75-80% of Ca2+ necessary for cardiac contraction. 4) local release causes calcium spark 5) summed calcium sparks creates a calcium signal. 6) Calcium drives contraction by binding to troponin. 7) relaxation occurs when calcium unbinds from troponin. 8) calcium is pumped back into sarcoplasmic reiculum for storage. 9) calcium is exchanged with sodium. 10) sodium gradient maintained by Na/K ATPase. **§ b1-adrenergic stimulation activates AC which creates cAMP which activates PKA - PKA then has 2 main actions: o Phosphorylates proteins in the myofibril. o Induces CICR in the SR by stimulating Ca2+ influx into SR. The majority (75-85%) of Ca2+ is from CICR. § PMCA (ATPase Ca2+ channel) and NCX (Na+/Ca2+ exchanger) mediate removal of Ca2+ from the cells.**

Epilepsy: Seizure types

1) General Seizures Begins simultaneously in BOTH hemispheres of brain. **Seizure types & Symptoms: a) Tonic-clonic seizures: loss of consciousness --> muscle stiffening--> jerking/twitching --> deep sleep --> wakes up. b) Absence seizures: brief staring episodes with behavioural arrest. Also lose muscle function and fall to ground. c) Tonic/atonic seizures: sudden muscle stiffening/sudden loss of muscle control. d) Myoclonic seizures: sudden, brief muscle contractions e) Status epilepticus: > 5 min of continuous seizure activity. Most dangerous type. 2) Partial/ focal Seizures: Begins within a particular area of brain and may spread out. Becoming more common --> can result from traumatic brain injury. **Seizure types & Symptoms: a) Simple: retained awareness/consciousness b) Complex: impaired awareness/consciousness

§ Darren attends his optician for a routine eye test and to buy a new pair of spectacles. Part of the test shows he has increased intraocular pressure. Slightly alarmed by his optician's insistence that he seek treatment, Darren gets an appointment to see his GP, who debates over the optimal treatment for his glaucoma, taking into account the fact that he has both diabetes and asthma. 1) What causes the rise in intraocular pressure with age and why is it important that the condition is treatment promptly? 2) Which treatment options should Darren avoid, given his clinical history?

1) Glaucoma occurs if the trabecular meshwork which drains aqueous humour becomes partially blocked, preventing normal fluid drainage. This results in an increase in intraocular pressure which, in turn, can result in damage to the optic nerve and the retinal tissue. If the pressure is not reduced, this can cause blindness. Treatments are predicated on improving drainage, and thereby reducing the pressure. 2) a) Beta blockers - possible potential for bronchospasm and can also be dangerous for diabetics. b) Muscarinic agonists - possible potential for bronchospasm. c) Prostaglandin analogues - Contrasting evidence for the effect on asthmatics. Some studies show that asthmatic symptoms reduced after discontinuance of PAs.

Interaction of local anaesthetics with sodium channels

1) Hydrophilic pathway (top pathway - channel open): 1. The drug remains in equilibrium between ionised and unionised forms (as all LAs are weak bases). 2. Unionised form - can pass across membranes but CANNOT have any action. 3. Ionised form - is needed to have an action but CANNOT pass across membranes. 4. This pathway is use-dependent as the channels need to be open for the cation drug to access the VGSCs. 2) Hydrophobic pathway (bottom pathway, much less important): 1. Lipid-soluble drugs can access the hydrophobic pathway and drop into the channel even when the channel is closed (they are NOT use-dependent). **LAs work from inside the neurone.

Administration of cocaine

1) IV - 100% BA 2) inhalation - less bioavailability as pKa of cocaine is high (8.7); smoke is acidic; more unionised in alkaline conditions and more ionised in acidic conditions. hence once inhaled, won't diffuse across mucous membranes greatly. 3) intranasal - pretty similar to inhalational. 4) oral - gut is acidic, so cocaine ionised and poorly absorbed. more delayed. § Administration: o IV has a fast onset of action and a short-lasting high. 100% BA. o Smoking, nasal and oral has a slower onset. § pKa = 8.7 and so cocaine is ionised in the GIT. § Slower absorption and a prolonged action. o speed of onset with IV and inhalation are nearly identical.

1) With regard to bronchodilation, identify the precise location where adrenaline would produce this effect? 2) How would the properties of affinity and efficacy contribute to this effect?

1) In order to produce an effect, adrenaline needs to bind to and activate the relevant adrenoceptor in this case - in the lung. The injected adrenaline will enter the venous system and be returned to the heart before it is ejected into the systemic circulation. As blood passes through the pulmonary circulation, adrenaline can diffuse out of the capillaries and act on adrenoceptors on bronchial smooth muscle. In this case, receptor activation leads to bronchodilation. In the case of adrenoceptors, they are widely distributed throughout the body, and adrenaline will diffuse into other tissues and activate adrenoceptors in these tissues to produce the relevant response e.g. increase heart rate in the heart. 2) The affinity and efficacy of drugs only influence drug-receptor interactions. With regard to the injected adrenaline and its effect in the lung, affinity and efficacy are not important until after the adrenaline has crossed the lung capillary and can bind to adrenoceptors on bronchial smooth muscle. At this point, the affinity of adrenaline for the adrenoceptor will determine the strength of the adrenaline-receptor binding and the efficacy of adrenaline will determine the strength of the adrenaline-receptor response (i.e. downstream signalling response).

Drugs targeting Glutamate exocytosis & receptors in epilepsy

1) Levetiracetam: a) Pharmacodynamics: •Binds to synaptic vesicle associated protein (SV2A) --> preventing binding of glutamate to pre-synaptic neurone membrane and also glutamate release b) Pharmacokinetics: •Fast-onset (1 hour); half-life (10 hours - hence given more frequently) c) Indications: •Myoclonic seizures 2) Topiramate: a) Pharmacodynamics •Inhibits NMDA & kainate receptors. •Also affects VGSCs & GABA receptors. b) Pharmacokinetics •Fast-onset (1 hour); long half-life (20 hours) c) Indications •Myoclonic seizures • ALSO used in treating some neuropathic pain.

MAO inhibitors and COMT inhibitors in PD treatment

1) MAO Inhibitor: a) Deprenyl (Selegiline): Can be given on its own in the early stages of the disease or it can be given in combination with L-DOPA. Such a combination can reduce the dose of L-DOPA required by depending on the patient. Hence, can reduce side effects experienced by the patients because you can reduce the dose of L-DOPA required to treat the condition. b) A newer MAOB inhibitor - Rasagiline - has been shown to have neuroprotective effects in-vivo by inhibiting apoptosis. Early results from clinical trials possibly indicate that this drug may also slow the disease down? Side Effects (rare) 2) COMT Inhibitors - Tolcapone, Entacapone: The COMT inhibitors, like the MAO inhibitors, prevent the breakdown of dopamine within the brain. However, the COMT enzyme is also present in the periphery and convert L-DOPA to 3-OMD and L-DOPA compete with the same transport mechanism to cross the blood brain barrier and gain access to the brain.

MAO two types (monoamine oxidase)

1) MAO-A : breaks down NA & 5-HT preferentially 2) MAO-B : breaks down DA preferentially

Metabolites of opioids

1) Morphine - Morphine-6-G glucuronide (M6G) (10% of metabolites), morphine 3-G glucuronide o active in ability to cause euphoria but not respiratory depression (which is good!) 2) methadone and fentanyl - no active metabolites, so once metabolised that's it, lose activity. 3) heroine and codeine - are pro-drugs; their active metabolite is morphine 4) methadone and fentanyl have very different clearance rate and persists in adipose tissue and slowly released into bloodstream over hours; methadone metabolised slowly so lasts longer, fentanyl metabolised faster. o Morphine has a greater affinity for m2-receptors than M6G which is related to adverse effects. § Fentanyl undergoes fast metabolism - CYP3A4 enzymes. § Methadone undergoes slow metabolism - 6 CYP enzymes. · Usually, best tolerated opioid is the one that undergoes CYP-mediated metabolism. § Codeine --> morphine - only 5-10% of codeine is metabolised to produce morphine as there are activating (slow) and inactivating enzymes found in the liver: a) Activation to morphine is slow via CYP-2D6 (O-dealkylation) - some people have a polymorphism in this enzyme so don't respond to codeine. b) Deactivation via CYP-3A4 (metabolises and deactivates codeine) at quite a rapid speed. Hence, 90% metabolised and 10% converted to active morphine. § Most opioids are metabolised by CYP-2D6 and CYP-3A4 in the liver.

Mr Brown, a relatively fit 50 year old, starts to suffer from chest pain following exertion. His GP prescribes sublingual GTN spray and refers Mr Brown to a specialist clinic for further investigations. 1) What is the likely diagnosis of Mr Brown's condition? 2) The results of Mr Brown's investigations are all within normal limits with the exception of his cholesterol level, which is 9.6 with an LDL cholesterol of 7.5. Mr Brown is prescribed three different drugs - simvastatin, bisoprolol and aspirin. Why has Mr Brown been prescribed these drugs and by what mechanisms do these act?

1) Mr Brown is likely to be suffering from angina. Angina occurs when the oxygen supply to the myocardium is insufficient for its needs. The pain usually has a very characteristic distribution occurring in the chest, arm and neck and is brought on by exertion or excitement. o Stable angina is a predictable pain on exertion and is due to a fixed narrowing of the coronary vessels by atheroma. o Unstable angina is characterised by pain following less and less exertion culminating in pain on resting. This is usually associated with a thrombus (derived from an atheromatous plaque) partially occluding the vessel(s) o Glyceryl trinitrate is an organic nitrate, which acts by inducing marked vascular relaxation via the release of nitric oxide. GTN can be used prophylactically immediately before exertion. 2) o Mr Brown has a high cholesterol level. Low density lipoproteins (LDL) provide the main circulating source of cholesterol in the body. o The definition of pathological hypercholesterolaemia is somewhat arbitrary as the normal range of plasma cholesterol concentration varies in different populations. However in Britain 25% of middle-aged people exhibit cholesterol concentrations higher than 6.5 mmol/l and there is a continuous gradation of risk with increased cholesterol concentration, with no threshold. o Hypercholesterolaemia is associated with a markedly increased risk of ischaemic heart disease, arising from rupture of atheromatous plaques in the coronary arteries and leading to myocardial infarction. o Simvastatin belongs to a class of drugs known as the statins, which act by specifically inhibiting the enzyme HMG-CoA reductase. o The conversion of HMG-CoA to mevalonic acid is the rate-limiting step in cholesterol synthesis in the body and is catalysed by the enzyme HMG-CoA reductase. o The fall in cholesterol synthesis produces a compensatory increase in expression of LDL receptors on the hepatocyte and increased clearance of circulating levels of LDL cholesterol. NB HMG-CoA reductase is active when blood glucose is high. o The rise in heart rate is one of the main precipitating factors for angina, consequently the use of Bisoprolol, a β-blocker, is an appropriate treatment.β-blockers act as competetitive antagonists of catecholamines at β-adrenoreceptors thereby reducing heart rate and contractility. The effects are most marked during exercise. o Arachidonic acid is converted to thromboxane A2 by the action of cyclooxygenase. Thromboxane is produced by platelets and promotes platelet aggregation. o Aspirin irreversibly inhibits cyclooxygenase activity thereby reducing the risk of thromboembolism: Prophylactic use.

NSTEMI vs STEMI

1) NSTEMI: •Non-ST elevated myocardial infarction (MI) •'White' thrombus --> PARTIALLY occluded coronary artery •Treatment: antiplatelets 2) STEMI: •ST elevated myocardial infarction •'White' thrombus --> FULLY occluded coronary artery •Treatment: antiplatelets & thrombolytics Caused by: 1) Damage to endothelium 2) Atheroma formation 3) Platelet aggregation **white vs red thrombus: o red thrombi e.g. in DVT (vein) tend to be RBC rich and better treated with anticoagulants (LMWH and warfarins). o white thrombus: forms in artery. tend not to form inside actual blood vessel wall, high content of foam cells (macrophages ingested into thrombus and take on lots of cholesterol --> white appearance). treated with antiplatelets and thrombolytics.

Nicotine pharmacodynamics

1) Nicotine binds to nicotinic receptors and stimulates Na+ transport. 2) Cardiovascular: o Stimulation of the nAChRs leads to a SNS activation (CNS & adrenals). § Increased - HR, SV. § Vasoconstriction of skin arterioles. § Vasodilation of coronary arterioles, skeletal muscle arterioles. o Increased lipolysis, FFAs, VLDLs, decreased HDL. o Increased TXA2, reduced NO. § Long-term use --> Cardiovascular disease. 3) Euphoria: o nAChRs are found on the soma of the dopamine nuclei in the VTA. o Stimulation of these receptors stimulates DA release in the NAcc. 4) Metabolic: o Nicotine leads to an increase in metabolic rate (and decreased appetite). o So, after STOPPING smoking, this can lead to a GAIN in weight (no longer have a faster metabolism). 5) Neurodegenerative disorders: o Parkinson's disease - increases brain CYPs (neurotoxin enzymes) --> increased breakdown of neurotoxins. o Alzheimer's disease - decreases beta-amyloid toxicity AND decreases amyloid precursor protein (APP) § Nicotine seems to be PROTECTIVE against both diseases.

4 stages of bacterial protein synthesis that can be targeted

1) Nucleic Acid Synthesis 2) DNA replication 3) RNA synthesis 4) Protein synthesis 1) Nucleic acid synthesis: Nucleic acids are the building blocks of prokaryotic (and eukaryotic) DNA; therefore their synthesis is essential for cell survival and cell division. Tetrahydrofolate (THF) is a critical co-factor involved in the production of numerous amino acids and thymidylate (which is required for uracil synthesis). And there are subtle differences between THF production in prokaryotes that can be exploited by pharmacological reagents. § THF production pathway in prokaryotes: involves the intermediary dihydropteroate (DHOp). The enzyme DHOp synthase is not functional in humans and is targeted by the sulphonamide (e.g. sulfadiazine) group of antibiotics. However, these antibiotics are no longer used readily mainly due to the development of bacterial resistance. Trimethoprim targets the bacterial dihydrofolate (DHF) reductase enzyme with a far greater affinity than the human isoform. It is often used in conjunction with the sulphonamide drug (sulphamethoxazole) in the compound preparation co-trimoxazole but is also prescribed alone mainly for the treatment of urinary tract infections. 2) DNA Replication: DNA replication is the process by which the nucleotide sequence of DNA is copied into an exact complementary sequence, which is required for cell division. The process requires an elaborate interplay between numerous different proteins but for the purpose of this lecture we will focus on the DNA gyrase enzyme. DNA gyrase is a type II topoisomerase, which cuts DNA strands thus releasing the tension from supercoiling and therefore allowing access to all the proteins involved in transcription. DNA gyrase is NOT present in humans and is targeted by the Quinolone (e.g. ciprofloxacin) group of antibiotics. They are generally effective against both Gram negative and Gram positive bacteria (broad spectrum) but they are contraindicated in children and individuals with epilepsy. 3) DNA transcription: DNA transcription is the 'process whereby one strand of a DNA molecule is used as a template for synthesis of a complementary RNA by RNA polymerase'. The complementary RNA (known as messenger (m)RNA) is subsequently utilised for the production of proteins. In bacteria there is only one RNA polymerase responsible for the entire process (as opposed to eukaryotes, who have multiple types of RNA polymerase) and this enzyme is targeted by the Rifamycins (e.g. rifampicin), which are primarily used to treat mycobacterial infections (e.g. tuberculosis). 4) Protein synthesis: The process of protein synthesis, or translation, can be defined as 'the ribosome-mediated production of a polypeptide whose amino acid sequence is specified by the nucleotide sequence in an mRNA.' There are a number of antibiotics that are known to prevent bacterial protein synthesis and these are outlined in table 1.

MUSCARINIC RECEPTOR ANTAGONISTS - Clinical Uses

1) Ophthalmic - pupil dilates - used to exam back of the eye for retina examination 2) anaesthetic premedication - blocks production of saliva (so no secretions to block airway), blocks heart rate and contractility, blocks trachea and bronchioles and sedation (e.g. with hyoscine). blocks parasympathetic effect 3) neurological - motion sickness. motion sickness is sensory mismatch; when visual info from eyes and labyrinth from ear relaying balance, mismatch, get vomiting which is transmitted by cholinergic nerve to vomiting centre. so hyoscine would diffuse into bloodstream, into vomiting centre and block the muscarinic receptor 4) Parkinsons - is loss of dopaminergic neurones from substantia nigra into striata. D1 receptors are dopamine receptors that respond to dopamine and control fine muscle movement. So try to upregulate D1 receptor to increase sensitivity to the limited dopamine being released. Muscarinic receptors (M4) have suppressive effect on D1 receptor. Block M4R to make D1R more receptive and effective. 5) Asthma/ obstructive airway disease - block receptor that wants to constrict --> bronchodilation. Atropine is typical drug, ipratropium bromide is one used in asthma to try and localise effects to reduce side effects for systemic reach. it's more polar so can't cross lipid membrane. 6) GIT - IBS. Parasympathetic stimulates motility and tone. so try to slow gut down. M3 receptor antagonist to try and limit effects of IBS.

How is cannabis usally taken?

1) Oral - 5-15% THC delivered; delayed onset/slow absorption (0.5-2h) but duration is prolonged due to slowabsorption from the gut. first pass metabolism. 2) Inhalation (smoked) - 25-35% THC delivered. this is typical for most of drug (because typically exhale 50%, and need to get the drug right till the alveoli). **Metabolised in the liver. A major metabolite is 11-hydroxy-THC (a potent cannabinoid itself). Over 20 other metabolites are known. ** Partly excreted in urine (25%) but mainly into the gut (65%) from which they are reabsorbed, further prolonging their actions.

Drugs influencing myocardial oxygen supply/demand

1) Organic nitrates - directly supply NO. § Increase cGMP which stimulates K+ channel opening and relaxation directly. sGC (soluble guanylate cyclase) forms cGMP which causes relaxation and potassium channel opening (--> hyperpolarisation) 2) Potassium channel openers. § Stimulates hyperpolarisation (ability of coronary arteries to contract is impaired). ** These drugs decrease preload/afterload (demand) and increase oxygen supply(INCREASE CORONARY blood flow): o Vasodilation = decreased afterload (less TPR). o Venodilation = decreased preload

Nicotine - pharmacodynamics - neurodegenerative disorders

1) Parkinson's disease - increases brain CYPs (neurotoxin enzymes) --> increased breakdown of neurotoxins. 2) Alzheimer's disease - decreases beta-amyloid toxicity AND decreases amyloid precursor protein (APP) § Nicotine seems to be PROTECTIVE against both diseases.

Pharmacodynamic, pharmacokinetic and pharmaceutical meaning

1) Pharmacodynamics - drug's effects on the body - e.g. receptor site dynamics. § Additive, synergistic, or antagonistic effects from co-administration. o Synergistic actions of antibiotics - use of two ABs will increase the effect more than their separate contributions (i.e. 2+2=5) OR they antagonise each other. o Overlapping toxicity - ethanol and benzodiazepines. o Antagonistic effects - anticholinergic medications. 2) Pharmacokinetics - body's effects on the drug - e.g. absorption, distribution, metabolism, excretion. § Alteration in absorption - CHELATION: o Irreversible binding in the GI-tract, for example, antibiotics to metal ions or calcium to form chelates that prevent absorption of the antibiotic. § Protein-binding interactions - not usually clinically significant but some are (e.g. warfarin). o Warfarin is 99% albumin-bound so anything to decrease that will increase the free warfarin so there is more anti-coagulative effects. § Drug metabolism and excretion: o Drugs can either be (1) directly excreted, (2) undergo Ph1 metabolism and be excreted, (3) undergo Ph1 and Ph2 and then be excreted or (4) only undergo Ph2 and then be excreted. 3) Pharmaceutical - drug interactions outside the body - e.g. in IV infusions.

Drug metabolism involves which two kinds of biochemical reaction?

1) Phase 1 - main aim is to introduce a reactive group to the drug (increase polarity) - tend to be oxidation/reduction/hydrolysis reduction 2) Phase 2 - main aim to to add a water soluble conjugate to the reactive group (make it easier to excrete)

Presentation, investigations, pathophysiology and treatment of H.pylori infection

1) Presentation: •Epigastric pain, burning sensation that occurs after meals 2) Investigations & Diagnosis: a) Carbon-urea breath test - positive (detects urea in breath --> means likely to have H.pylori) b) Stool antigen test - positive (confirms H. pylori) •Hence, H Pylori positive peptic ulcer. 3) Pathophysiology: Helicobacter pylori (H pylori) •Dissolves mucus layer in bits produced by epithelial cells •Causes epithelial cell death •Increased acidity --> peptic ulcer (also issue if severe, may get blood loss and if severe bleeding this is emergency) 4) Treatment: 1) Amoxicillin & Clarithromycin/Metronidazole (used for gram -ve) - Antibiotics to treat H. pylori bacteria 2) Proton Pump Inhibitor (PPI) - reduces acid production *so triple therapy (2 antibiotics and one PPI)

Which HT drugs for different conditions

1) RAS vs CCBs •CCBs decrease SBP more than RAS inhibitors •RAS inhibitors decrease heart failure •RAS inhibitors increase stroke •No difference for all-cause death 2) RAS vs thiazides •Thiazides decrease SBP more than RAS inhibitors •RAS inhibitors increase heart failure •RAS inhibitors increase stroke •No difference for all-cause death 3) RAS vs beta-blockers •No difference in SBP reduction •RAS inhibitors decrease CV events •RAS inhibitors decrease stroke •No difference for all-cause death

What are the three main therapeutic effects of NSAIDs?

1) Relief of mild-to-moderate pain (analgesic) »Toothache, headache, backache »Postoperative pain (opiate sparing) »Dysmenorrhea (menstrual pain) 2) Reduction of fever (antipyretic) »Influenza 3) Reduction of inflammation (anti-inflammatory) »Rheumatoid arthritis »Osteoarthritis »Other forms of musculo-skeletal inflammation »Soft tissue injuries (strains and sprains) »Gout. **§ Clinical uses: o Analgesic - toothache/headache, post-op pain (opiate-sparing), menstrual pain. o Anti-pyretic - influenza. o Anti-inflammatory - rheumatoid arthritis, osteoarthritis, gout, soft-tissue injuries. o Anti-aggregatory drug to inhibition platelet aggregation in patients who are at risk of stroke or myocardial infarct § Note NSAIDs are widely used and available OTC. § Deaths from NSAIDs are on par with road traffic accidents (half due to GI upsets, and half due to CVS issues). o ~2000 deaths/annum in 2011.

Adrenaline - unwanted actions

1) Secretions - reduced and thickened mucous 2) CNS - minimal 3) CVS effects - depends on how old you are -tachycardia, palpitations, arrhythmias -cold extremities (from vasoconstriction), hypertension -overdose - cerebral haemorrhage, pulmonary oedema 4) GIT - minimal 5) Skeletal muscle - tremor

Routes of Administration of LAs

1) Surface anaesthesia - spray or powder form: Sore throat relief. o Mucosal surfaces - e.g. mouth, bronchial tree. o need high concentrations for effect --> can lead to systemic toxicity. 2) Infiltration anaesthesia - SC injection: Post-surgery sutra LA analgesia. o Used in minor surgeries and SC injection directly into tissues (the sensory nerve terminals). o Adrenaline is co-administered (but NOT administered extremities as don't want to cut off blood supply to digits) to vasoconstrict to: a) Slow down diffusion of LA away from the site of injection - lower concentration of LA needed. b) Reduce systemic toxicity. c) Minimises bleeding 3) IV regional anaesthesia - IV injection distal to a pressure cuff: Trigger finger repair. o Used in limb surgery. o Systemic toxicity if the cuff is released prematurely. Cuff keeps it localised 4) Nerve block anaesthesia - injection: Tooth extraction. o Injection close to nerve TRUNKS - e.g. dental nerves. requires a lot of skill. o Widely used - low doses and slow onset of action. o Vasoconstrictor co-administration often. 5) Spinal anaesthesia - intrathecal (sub-arachnoid space injection into CSF): Hip replacement: o Injection close to spinal ROOTS - e.g. lower limb, abdominal, pelvic surgery. o requires Low dose. o Reduces BP and so can cause prolonged headache (hence need to monitor BP). o Glucose can be added to increase specific gravity of injection so the LA doesn't travel up the CSF to the brain and can control where in spine want the effect. 6) Epidural anaesthesia - injection into fatty tissue of epidural space: o Injection close to spinal ROOTS - e.g. lower limb surgery (like spinal anaesthesia), painless childbirth. o Cons - slower onset and higher doses required (hence may get systemic toxicity) o Pros - more restricted action, less effect on BP.

Types of antidepressants

1) TCAs e.g. Amitriptyline 2) MAOIs e.g. Phenelzine 3) SSRIs e.g. Fluoxetine

Types of ADRs

1) Type A: Augment/extend the pharmacological effect. § Usually predictable and dose-dependent, represents 2/3rds of ADRs. § Paracetamol has a threshold below which it has minimal side effects (and then exceeding this, side effects rapidly increase due to liver damage). Digoxin just has a dose-dependent line with constant increasing SEs. § E.G. Atenolol + heart block, anticholinergics and dry mouth, NSAIDs + peptic ulcers. 2) Type B: Bizarre - Idiosyncratic or Immunologic reactions. § Unpredictable, rare, and include allergy and "pseudo-allergy". § rare (even very rare) and unpredictable § E.G. Chloramphenicol (antibiotic) + aplastic anaemia and BM failure, ACE inhibitors + angioedema (swelling of lips, tongue, bronchoconstriction and potentially HF) § Many serious ADRs are totally unexpected e.g. Herceptin (used for breast cancer) and cardiac toxicity. 3) Type C: Chronic - Long-term use side effects: § Involves dose accumulation. § E.G. Methotrexate (immunosuppressant and in cancer) + liver fibrosis, antimalarials and ocular toxicity 4) Type D: Delayed - Delayed effects: § delayed effects (sometimes dose independent) § Carcinogenicity - e.g. immunosuppressants. § Teratogenicity - e.g. thalidomide. 5) Type E: End of treatment side effects. BDP = benzodiazepines. § Withdrawal reactions - patient cannot make endogenous supply - opiates, corticosteroids, BDPs (benzodiazepines). § Rebound reactions - disease gets worse when drugs stopped - clonidine, b-blockers, corticosteroids. § "Adaptive" reactions - adapted body reactions to drugs - neuroleptics (antipsychotics, major tranquilisers) **** Classification overview: o A - augmented pharmacological effect. o B - bizarre. o C - chronic. o D - delayed. o E - end-of-treatment.

Calcium Channel Blockers- side effects

1) Verapamil (rate-limiting): § Bradycardia & AV-block - heart Ca2+ channels blocked. § Constipation - gut Ca2+ channels blocked which drive gut motility. 2) Dihydropyridines (non-rate-limiting): § Ankle oedema - vasodilation means more capillary pressure in extremities. § Headache/flushing - vasodilation. § Palpitations - reflex SNS adrenergic activation due to vasodilation. 3) Potassium channel openers + Nitrates: o Ankle oedema - vasodilation means more capillary pressure in extremities. o Headache/flushing - vasodilation

The Typical Life-Cycle of a Virus

1) Viral attachment & entry: To enter a host cell a virion usually attaches itself through interaction with a membrane receptor. The most common receptors are usually proteins (e.g. CD4 receptor). 2) Entry: The three most common methods employed by viruses to gain entry into a host cell are:a) Clathrin-mediated endocytosis. b) Caveolar endocytosis c) Plasma membrane fusion. 3) Uncoating: During the process of transportation from the host membrane to the destination of the viral particles it is imperative that the viral capsid is removed. This occurs so that the genetic material can come into direct contact with the cellular machinery that it will utilise for replication. The degradation of the capsid involves a variety of different proteins and enzymes, which are produced by both the host cell and the virus. 4) Replication: The process of viral replication varies greatly between different viruses and can occur in either the host cell cytoplasm or within the nucleus. The method of replication is dependent upon the type of nucleic acid making up the viral genome: a) Positive (+ve) single-stranded RNA (ssRNA): These can produce proteins (i.e. induce translation) directly by utilising the hosts' ribosomes. b) Negative (-ve) ssRNA: These cannot produce protein directly and must contain the appropriate transcriptase allowing the host ribosome to create the complementary +ve RNA strand. c) Diploid +ve ssRNA retroviruses: These contain a reverse transcriptase enzyme allowing the host cell to produce DNA from the viral genome. d) Double-stranded RNA viruses: These contain all the necessary templates to produce the proteins and RNA templates required for replication. e) DNA viruses: These viruses generally have the means for transportation into the host nucleus. 5) Assembly: Once the virus has acquired the means to replicate its genome it must be packaged into the capsids and nuclear envelopes required for a mature virion. For nonenveloped viruses this process just requires the construction of the capsid. With enveloped viruses the process of assembly is closely associated with the release stage and involves the formation of 'docking stations' within the host membrane by viral proteins. Once the viral proteins have replaced the host proteins in the membrane the nucleocapsid attaches itself (i.e. docks) to the inner surface of the membrane. 6) Release: The ejection of the virus particles from the host cell occurs either by disintegration of the host cell or a process known as budding where the host cell remains intact. For enveloped viruses once the nucleocapsid is attached to the 'docking station' it becomes wrapped up within the patch of membrane and 'buds' off into the extracellular environment.

a1-receptors and a2-receptors

1) a1-receptors: •Gq-linked •Postsynaptic on vascular smooth muscle 2) a2-receptors: •Gi-linked •Presynaptic auto-receptors inhibiting•Non-selective α antagonists cause a rapid fall in arterial pressure, as α1-receptors are the main mediators of peripheral resistance •This fall in blood pressure is due to subcutaneous vasodilation, leading to an increased blood flow through cutaneous and splanchnic vascular beds NA release **•Non-selective α antagonists cause a rapid fall in arterial pressure, as α1-receptors are the main mediators of peripheral resistance •This fall in blood pressure is due to subcutaneous vasodilation, leading to an increased blood flow through cutaneous and splanchnic vascular beds

Potential outcomes with phase 1 metabolism

1) active parent drug --> inert metabolite 2) active parent drug --> active metabolite (prolongs effects) 3) inactive parent drug --> active metabolite (prodrug)

Sites of NMJ drug action

1) central process (where AP generated in spinal cord) : spasmolytics e.g. diazepam/valium, baclofen (gabaergic drugs) 2) conduction of nerve AP in motor neruone e.g. local anaesthetics (block sodium channels, reduce propagation of AP, and not reach thalamus and somatosensory cortex); if inject close to motor fibre and get some effect and get relaxation; but try to keep away from motor fibres 3) Ach release e.g. hemicholinium, Ca2+ entry blockers, neurotoxins (e.g. botulinim - can be used in botox to paralyse muscle in forehead) 4) depolarisation of motor-end plate --> AP initiation e.g. tubocurarine, suxamethonium 5) propagation of AP along muscle fibre + muscle contraction e.g. spasmolytics (dantrolene) - reduce release of calcium ions from sarcoplasmic reticulum ** § Spasmolytics - e.g. Diazepam, Baclofen. o Target central processes within the nerve cell. o Spasmolytics relieve spasm of the muscles. § Local anaesthetics. o Inhibit the influx of sodium and so reduce the propagation of the AP along the nerve. § Hemicolinium, Ca2+-entry blockers, neurotoxins. o Inhibit re-uptake of choline. § Tubocurarine, suxamethonium. o These react on the post-synaptic membrane. § Spasmolytics - e.g. Dantrolene.

Two types of cholinomimetic drugs

1) directly acting - act on muscarinic receptor 2) indirectly acting - acts on acetylcholinesterase in synaptic cleft

Other uses of adrenaline apart from anaphylactic shock?

1) heart - b1 - inotropic effect. treats cardiogenic shock - sudden inability of heart to pump sufficient oxygen-rich blood 2) lungs - b2 - Acute bronchospasm associated with chronic bronchitis or emphysema. In asthma (emergencies - i.m., s.c.) 3) BVs - a1 - maintains BP by vasoconstricting. with local anaesthetics, it will prolong action by vasoconstricting

Where are the tissue targets for anti-hypertensives?

1) heart - influence CO 2) arterioles - determine TPR 3) kidney - RAAS 4) Sympathetic nerves - release NA 5) CNS/ brain - determines blood pressure set point and regulates some systems involved in Blood pressure control & autonomic NS.

Beta blockers in heart and kidney

1) heart • decrease in HR & FOC - decrease in cardiac output o The heart does not have to work as hard - reduced blood pressure. so block receptors, decrease cAMP and PKA. decrease CO. 2) kidney: • decreased renin --> decrease angiotensin II (Ang II) release. Ang II - potent vasoconstrictor & increased aldosterone production. decrease blood volume and TPR o Blockade of the facilitatory effects of presynaptic β-adrenoceptors on noradrenaline release may also contribute to the antihypertensive effect.

The major routes of metabolism for this compound are shown below, identify the phase 1 and 2 reactions and name the enzymes/co-substrates involved.

1) hydoxylation (phase 1). enzyme: CYP450. co-substrates: NAPDH, O2 2) removing methanone (CH3-OH) and replacing with OH. hydrolysis of ester bond. phase 2. reaction: De-esterification. enzyme: Esterase 3) amino acid conjugation - phase 2. substrates: Glycine, Ligase, Acyl-CoA. 4) glucoronide conjugation - phase 2. Glucuronidation. enzyme: UDP-glucuronyltransferase. substrate: UDP-glucuronic acid. 5) reduction - phase 1 (could occur in GIT where not much oxygen; gut bacteria catalyse reaction). given as skin patch, so bypass GIT, so not too quickly metabolise and reaches blood stream. enzyme: nitroreductase. 6) N-acetylation - phase 2. enzyme: N-acetyltransferase. substrate: Acetyl-CoA. * reduction of the nitro group by bacterial nitroreductases in the gut would not be expected for skin patch administration. hence, acetylation in the liver of the resulting amino group would not occur. metabolism of the compound would be more limited and cytochrome P450s would be expected to play a larger role in removal of the parent drug via hydroxylation and subsequent conjugation or phase 2 reactions (e.g. glucuronidation)

Mrs Green is a 78 year old woman who complains to her GP of increasing tiredness, shortness of breath on exertion and swollen ankles. She is diagnosed as suffering from congestive heart failure. 1) What do you understand by the term congestive heart failure? 2) Mrs Green is prescribed frusemide and perindopril. What classes of drugs are these and how do they act? 3) On going back to her GP some months later she is prescribed another class of drug, which is to be introduced gradually, beginning at a low dose and titrating up. What class of drug is this likely to be and why is it introduced in this way?

1) i) Heart failure is a global term for the physiological state in which cardiac output is insufficient for the body's needs. This may occur when the cardiac output is low (often termed "congestive heart failure"). ii) Inability of cardiac output to balance the needs of the tissues, leading to fluid accumulation (eg. In lungs and lower limbs) Fluid overload is a common problem for people with heart failure, but is not synonymous with it. 2) i) Frusemide is a loop diuretic, reducing sodium and potassium reabsorption in the ascending limb of the loop of Henle. This leads to increased clearance of water, with the sodium, and reduced extracellular and circulating volume. This reduces oedema in affected tissues and reduces preload so improving cardiac performance. ii) Perindopril is an ACE inhibitor - as previously discussed. 3) This is likely to be a β-blocker. Catecholamine levels are known to increase in proportion to the severity of symptoms in patients with heart failure. Patients with the highest levels of norepinephrine have the least favorable prognosis. β-Blockers have been shown to be effective in heart failure that has been stabilised with an ACE inhibitor and diuretic. If introduced gradually in small doses they improve symptoms and survival. Beneficial effects probably by reduction of cardiac work, possibly other effects. If this drug is not given in the way described it can cause a disastrous decrease in cardiac output which may be fatal.

The plasma half-life of paracetamol in patients with liver damage due to overdosage is over twice that in normal human subjects after a therapeutic dose. Interpret this information given what you know about the metabolism of paracetamol.

1) overdosage --> saturate detoxification pathways 2) NAPQI too much 3) NAPQI will form protein adducts 4) cell death of hepatocytes 5) liver damage --> less capacity to detoxify compounds 6) longer half life of paracetamol * the major route of metabolism for the reactive intermediate, NAPQI, glutathione conjugation followed by transformation to a mercapturate will deplete glutathione levels. this results in increased covalent binding of NAPQI to proteins/ nucleic acids causing liver damage and/or the NAPQI can be reduced back to paracetamol thus increasing the half-life. all of the above result in a higher plasma level of unmetabolised paracetamol and hence longer half-life. o The impaired function of the liver results in compromised metabolism of paracetamol. One of the major routes of metabolism of paracetamol discussed above is sulphation. In paracetamol overdosage cases the body is depleted of sulphate and hence this route of metabolism is closed. Similarly, the glucuronidation of paracetamol may become saturated. This results in more paracetamol available for production of NAPQI. • The major route of metabolism for the reactive intermediate, NAPQI, glutathione conjugation followed by transformation to a mercapturate will deplete glutathione levels. • This results in increased covalent binding of NAPQI to proteins/nucleic acids causing liver damage and/or the NAPQI can be reduced back to paracetamol thus increasing the half-life. • All of the above result in a higher plasma level of unmetabolised paracetamol and hence longer half-life.

Strategies for targeted drug delivery

1) pH dependent polymer coating system (degrade when reaches right pH) 2) time dependent polymer coating system (degrade depend on how long been in gut) 3) pressure/osmotic controlled polymer coating system (semi-permeable membrane, when reaches lower intestine where more water, water enters and push layer pushes drug out) 4) prodrug based conjugates **now getting even more complex polymers which combine time and pH. •Potential to give better targeting of drugs to areas of inflammation and also reduce S/E.

In the case of oral administration of a medicine, several factors may influence bioavailability:

1) physicochemical characteristics - if drug is weak acid or weak base - affects when they are ionised and unionised. for weak acid: if pH is less than pKa, equilibrium lies towards unionised side (HA <--> H+ + A-), if unionised can be absorbed well as can pass the lipid barrier. if pH higher than pKa, drug is more ionised, and less of drug absorbed. for weak base: if pH less than pKa - lies towards ionised side (BH+ <--> B + H+). if pH = pKa, equilibrium is in middle so 50% of each side. 2) Gastrointestinal pH - influences how ionised a drug is and hence how well it is absorbed 3) passive diffusion is quick; active transport is slower 4) GIT motility: high motility - reduce time of substance in gut, so less bioavailability 5) particle size of drug - smaller is more dissolvable, more readily absorbed 6) physicochemical interaction between drug and gut contents - e.g.bacteria/acid - may metabolise or affect bioavailability

Example of phase 2 metabolism: paracetomal

1) sulphation (40-60% metabolism) - high affinity/low capacity - more likely to occur at low drug dosages 2) can also undergo glucuronation (20-30%) - drug needs to be electrophilic to be conjugated or biotransformed to an electrophilic conjugate in phase 2 metabolism. So how do we convert paracetamol to an electrophile? it undergoes oxidation and loses a hydrogen (phase 1 metabolism) to form NAPQ1 before undergoing glutathione conjugation (phase 2 metabolism)

Adrenoceptors distribution

1) β2-receptor mediated: a) Lungs, bronchodilation b) Blood vessels skeletal muscle - vasodilation 2) β1-receptor mediated: a) Kidney to cause renin secretion b) The heart to cause increased heart rate and contractility 3) α1-receptor mediated: a) Blood vessels of the viscera to cause vasoconstriction

Use of Glucocorticoids in IBD

1)Ulcerative colitis: a) Strong evidence that aminosalicylates superior b) Glucocorticoids not recommended 2) Crohn's Disease: a) GCs drugs of choice for inducing remission b) Budesonide preferred if mild; prednisolone if more severe c) Avoid as maintenance therapy due to side effects

Manipulation of microbiome in IBD - 4 therapies

1. Exclusive enteral nutrition (EEN) Ø Liquid diet Ø Allows "resting" of the mucosa and recovery of the gut flora Ø Unpalatable and hard to maintain Ø Only recommended for induction of remission if patient cannot take steroids 2) Probiotic therapies: Ø Different organisms have different effects so difficult to generalise Ø No evidence for probiotics in CD. Ø Weak evidence for maintenance of remission in UC 3) Faecal microbiota replacement (FMT) therapies Ø take faeces of healthy patient, extract some organisms and put into patient --> try to replace and outgrow unhealthy microbiota with healthy. Ø2 of 3 RCTs showed benefit in UC Ø But we are still unclear if changed microbiome is cause or effect of IBD. if it's cause then would make difference; but if effect, the new microbiota might just get outgrown again. 4) Antibiotic Treatment - Rifaximin Ø Interferes with bacterial transcription by binding to RNA polymerase and reduce inflammatory mediator mRNA. Ø Benefit shown in experimental models of IBD Ø May be microbiome modulator Ø Not absorbed from gut Ø Some evidence for sustained remission in moderate CD; no evidence for UC Ø Only recommended if complications of CD relating to infection (e.g. ulcers of abscesses)

Cell-Based Theory of Coagulation

1. Initiation - small scale production of thrombin. a. Targeted by ANTI-COAGULANTS. 2. Amplification - large scale production of thrombin (on platelet surfaces). a. Targeted by ANTI-PLATELETS. 3. Propagation - generation of fibrin strands by thrombin. a. Targeted by THROMBOLYTICS.

Types of atherosclerotic lesions

1. Lesion-prone location - Adaptive thickening. 2. Type 2 lesion - foam cells. 3. Type 3 lesion (preatheroma) - extracellular lipid. 4. Type 4 lesion (atheroma) - bigger core of extracellular lipid. 5. Type 5 lesion (fibroatheroma) - fibrous thickening. 6. Type 6 lesion (complicated lesion) - fissure & haematoma. •Complicated lesions often contain calcium. •Coronary artery disease can be detected by doing a CT scan of the heart -‐this will detect any calcium. •It is generally believed that the more calcium you have in the plaque, the more likely you are to be symptomatic

Most diuretics prescribed

1. Osmotic diuretics - e.g. mannitol - increases osmolality of tubular fluid so prevents water leaving 2. Carbonic anhydrase inhibitors e.g. acetazolamide - act in PCT 3. Loop diuretics e.g. frusemide (furosemide) - ascending limb 4. Thiazides e.g. bendrofluazide (bendroflumethiazide) - distal tubule 5. Potassium sparing diuretics e.g. amiloride, spironolactone - late DCT and CD.

What factors affect drug tolerance? (5)

1. Pharmacokinetic factors: increased rate of metabolism e.g. barbiturates; alcohol 2. Loss of receptors: - By membrane endocytosis; - Receptor "down-regulation" e.g. b-adrenoceptors Þ Note also: receptor "up-regulation" (denervation supersensitivity) 3. Change in receptors Receptor desensitization --> conformational change e.g. nAChR at NMJ 4. Exhaustion of mediator stores Amphetamine - snort amphetamine, drug locates neurons and binds to uptake transporter of NA and taken up into nerve terminal, gets into vesicles and causes release of NA - hence increases NA synaptic transmission; hence causes euphoric effect. if keep taking it, then lose mediated store (here is NA in terminals) 5. Physiological adaption - Homeostatic responses - Tolerance to drug side effects - The body physiologically adapts to administration of the drug over time. i. E.G. A drug causing a drop in BP could cause the RAS to activate in response to raise the BP. (e.g. thiazide diuretics have a limited effect on blood pressure after a while due to upregulation of Renin Angiotensin Aldosterone axis)

Describe the reactions in the diagram shown

1. Phase 1 - Oxidation - note that you are only adding an oxygen atom, not a hydrogen as it is already there. 2. Phase 2 - Hydrolysis - this is the reverse of esterification and is NOT demethylation. 3. Phase 2 - Amino acid conjugation - requires an amino acid. 4. Phase 1 - Nitro-reduction - using nitro-reductase. 5. Phase 2 - Acetylation. 6. Phase 2 - Glucuronidation - a large polar group added.

What are the two main types of depression?

1. Unipolar depression (Depressive disorder) - mood swings only in ONE direction: MORE CONCENTRATED ON a. Relatively late onset. b. 2 Types of unipolar depression: i. Reactive depression - distorted reaction to stressful life events, non-familial inheritance. very common. ii. Endogenous depression - unrelated to external events, familial pattern. c. All types of unipolar depression respond in the same way to the same drug treatments. 2. Bipolar depression (Manic depression) - oscillating between depression and mania: a. Less common and have an early adult onset. b. Strong hereditary tendency. c. Drug treatment includes Lithium - can stabilise the swings between mania and depression but lithium has a narrow therapeutic window. given orally as lithium carbonate and influences secondary messenger systems inside cells- reduces IP3 and cAMP inside cell. **mania is opposite to depression - increased activity, exuberance, potentially some aggression.

Factors influencing drug distribution

1. regional blood flow - more blood flow to tissue, gets more drug 2, extracellular binding (plasma-protein binding) 3. capillary permeability (tissue alterations - renal, hepatic, brain/CNS, placental) 4. localisation in tissues

Dopaminergic drugs: explain how drugs targeting the dopaminergic system are utilized in the treatment of schizophrenia, which symptoms they treat and discuss the side effects associated with these treatments

1.Chlorpromazine: phenothiazine causing antimuscarinic side-effects 2.Haloperidol: potent D2 antagonist causing extrapyramidal side-effects 3.Clozapine: very effective but causes agranulocytosis 4.Risperidone: effective but associated with weight gain & EPS 5.Quetiapine: low incidence of EPS 6.Aripiprazole: partial agonist, low incidence of hyperprolactinaemia

Antibiotic resistance: recall the mechanisms commonly used by bacteria to become resistant to drugs

1.Destruction enzymes - b-lactamases 2.Additional target - Different DHFR enzyme 3.Hyper-production - More DHFR enzyme 4.Changes to target - Changing DNA gyrase 5.Alterations in permeation - Increased efflux mechanisms

Parkinson's Disease treatment (1/3)

1.Dopamine replacement L-tyrosine (TYR) --> dopamine (DA) * don't give tyrosine as rate-limiting enzyme: Tyrosine hydroxylase (TH). Also don't give dopamine directly as has many periphery effects. ** GIVE Levodopa (L-DOPA) o Rapidly converted to DA by DOPA decarboxylase (DOPA-D). o Can cross blood-brain barrier (BBB) and acts of D2Receptors (Gi linked) o so neurones that are still there are producing lots more dopamine. o Peripheral breakdown by DOPA-D --> Leads to nausea & vomiting o Long-term side-effects: dyskinesias & 'on-off' effects. NOT disease-modifying - does not prolong life or halt progression of disease; it improves symptoms. **Adjuncts: 1) DOPA decarboxylase inhibitors: e.g. Carbidopa & Benserazide § *Do not cross BBB --> prevent peripheral breakdown of levodopa (to stop dopamine being formed in the periphery) § Reduce required levodopa dosage. 2) COMT inhibitors: Entacapone & Tolcapone: § increases amount of levodopa in the brain

GABAergic Synapse Neurotransmission

1.GABA can be released tonically (irrespective of neuronal excitation) & also following neuronal stimulation 2.GABA activates inhibitory post-synaptic GABAA receptors 3.GABAA receptors are chloride (Cl-) channels --> membrane hyperpolarisation (hence reducing neuronal activity) 4.GABA is taken up by GAT & metabolised by GABA transaminase (GABA-T) into glutamate

Anticoagulants to treat initiation of thrombosis

1.Inhibit factor IIa •Dabigatran (oral) - factor IIa inhibitor 2.Inhibit factor Xa •Rivaroxaban (oral) - factor Xa inhibitor 3.Increase activity of AT-III •Heparin (IV, SC) - activates AT-III (¯fIIa & ¯fXa) •Low-molecular weight heparins (LMWHs, e.g.Dalteparin) - activate AT-III (¯fXa) 4.Reduce levels of other factors •Warfarin (oral) - vitamin K antagonist •Vitamin K - required for generation of factors II, VII, IX & X

PHASE 1 - CYP450

1.It is a cycle so CYP450 enzyme is unchanged once reaction has finished 2.CYP450 is able to mediate the transfer of electrons due to its iron ion (two stable forms) 3.2nd reduction is the rate limiting step 4.Oxidation reactions generally start with a hydroxylation step catalysed by P450.

Clinical symptoms of Alzheimer's disease

1.Memory loss (MAJOR ONE)- especially recently acquired information 2.Disorientation/ confusion - forgetting where they are 3.Language problems - stopping in the middle of a conversation 4.Personality changes - becoming confused, fearful, anxious 5.Poor judgement - such as when dealing with money

Methyldopa summary

1.Methyldopa is a false transmitter 2.Less active at Beta/Alpha 1 receptor 3.Not metabolised by MAO 4.More likely to accumulate and displace noradrenaline in the vesicle. *Its mode of action differs slightly to that of NA: •Less active on α1-receptors, therefore less effective in causing vasoconstriction •More active on presynaptic α2-receptors, therefore the auto-inhibitory feedback mechanism operates more strongly therefore reducing neurotransmitter levels below normal •It also stimulates the vasopressor centre in brainstem to inhibit sympathetic outflow

Clinical presentation of Parkinson's Disease

1.Motor symptoms : resting tremor, bradykinesia, rigidity, postural instability (FOUR cardinal symptoms). resting tremor is early onset. rigidity is late onset. due to neurodegeneration of nigrostriatal tract. See motor symptoms after around 80% degeneration of nigrostriatal tract (quite late onwards) 2.Autonomic nervous system effects: olfactory deficits, orthostatic hypotension, constipation. These tend to be much earlier than motor symptoms. 3.Neuropsychiatric: sleep disorders, memory deficits, depression, irritability. *Braak staging of PD: start with olfactory and neuropsychiatric and then see motor deficits. then later see memory deficits, depression. hence can map the staging of PK by symptoms and catch it earlier to get better prognosis.

Beta blocker: propanalol

1.Non-selective •'Equal' affinity for b1 & b2 receptors •E.g. Propranolol 2. b1-selective (cardioselective) •More selective for b1 receptors •E.g. Atenolol 3. Mixed b- a blockers •a1 blockade gives additional vasodilator properties •E.g. Carvedilol - vasodilating effect 4.Other •Nebivolol: also potentiates NO - cardioselective, vasodilator •Sotalol: also inhibits K+ channels - interferes with cell hyperpolarisation

Prokaryotic protein synthesis inhibitors

1.Nucleic Acid Synthesis: a) Dihydropteroate (DHOp): Sulphonamides inhibit DHOp synthase. aren't used that much anymore due to resistance. b) Tetrahydrofolate (THF): Trimethoprim inhibits DHF reductase. **tend to use combo of Sulphonamides and Trimethoprim = co-trimoxazole. 2.DNA replication: DNA gyrase - •Fluoroquinolones (e.g. Ciprofloxacin) inhibit DNA gyrase & topoisomerase IV. 3.RNA synthesis RNA polymerase •The rifamycins (e.g. Rifampicin) inhibits bacterial RNA polymerase. Used in treatment of TB. 4.Protein synthesis Ribosomes •Inhibited by: § Aminoglycosides (e.g. Gentamicin) § Chloramphenicol § Macrolides (e.g. Erythromycin) § Tetracyclines

Prokaryotic protein synthesis

1.Nucleic Acid Synthesis: a) Dihydropteroate (DHOp): •Produced from paraaminobenzoate (PABA) by DHOp synthase •Converted into dihydrofolate (DHF) b) Tetrahydrofolate (THF) •Produced from DHF by DHF reductase •THF --> Important in DNA synthesis 2.DNA replication: DNA gyrase - aka Topoisomerase --> releases tension 3.RNA synthesis: RNA polymerase - •Produces RNA from DNA template •Differ from eukaryotic RNA polymerase 4.Protein synthesis Ribosomes •Produce protein from RNA templates •Differ from eukaryotic ribosomes

Bacterial cell wall synthesis

1.Peptidoglycan (PtG) synthesis: § occurs in cytoplasm § A pentapeptide is created on N-acetyl muramic acid (NAM) § N-acetyl glucosamine (NAG) associates with NAM forming PtG. § So pentapeptide + NAM+ NAG = Ptg 2.PtG transportation: •PtG is transported across the membrane into periplasm by bactoprenol (found within cell membrane) 3.PtG incorporation: •PtG is incorporated into the cell wall when transpeptidase enzyme cross-links PtG pentapeptides

Effects of LAs

1.Prevent generation and conduction of APs 2.Do NOT influence resting membrane potential 3.May also influence channel gating e.g. hold an inactivated state in a channel. Also lower surface tension. 4.Selectively block: ØSmall diameter fibres - e.g. nociceptive pain fibres. ØNon-myelinated fibres- pain fibres are often small (Ad-fibres) and unmyelinated (C-Fibres). **LAs are weak bases (pKa 8-9). So are mostly ionised and so less pass into the axons of neurones. As they have a high pKa, this means they are 'use-pH-dependent'. o INFECTED TISSUES are normally slightly acidic and so the LA is less effective as more will be ionised and less can enter neurones.

Abciximab

1.Prevent platelet activation/ aggregation: •Clopidogrel (oral) - ADP (P2Y12) receptor antagonist 2.Inhibit production of TXA2: •Aspirin (oral) - irreversible COX-1 Inhibitor •NB: High doses no more effective BUT more side-effects 3.Prevent platelet aggregation: •Abciximab (IV, SC) - monoclonal antibody that targets GpIIb/IIIa •Limited use AND only by specialists

Anti-platelet examples

1.Prevent platelet activation/ aggregation: •Clopidogrel (oral) - ADP (P2Y12) receptor antagonist 2.Inhibit production of TXA2: •Aspirin (oral) - irreversible COX-1 Inhibitor •NB: High doses no more effective BUT more side-effects 3.Prevent platelet aggregation: •Abciximab (IV, SC) - monoclonal antibody that targets GpIIb/IIIa •Limited use AND only by specialists

Clopidogrel

1.Prevent platelet activation/ aggregation: •Clopidogrel (oral) - ADP (P2Y12) receptor antagonist 2.Inhibit production of TXA2: •Aspirin (oral) - irreversible COX-1 Inhibitor •NB: High doses no more effective BUT more side-effects 3.Prevent platelet aggregation: •Abciximab (IV, SC) - monoclonal antibody that targets GpIIb/IIIa •Limited use AND only by specialists

Treatment failures for AD

1.g-secretase inhibitors Tarenflurbil & Semagacestat: a) Tarenflurbil binds to amyloid precursor protein (APP) molecule (enantiomer of ibuprofen). b) Semagacestat is a small molecule g-secretase inhibitor. actually made people worse. 2) b-amyloid plaques: a) Bapineuzumab & Solanezumab: •Humanised monoclonal antibodies b) Aducanumab? - targets beta amyloid differently to Bapineuzumab & Solanezumab - targets beta amyloid fibrils and monomers. could potentially be effective. Humanised monoclonal antibody. c) Vaccines also in early stages of development. 3.Tau inhibitors: a) Methylene blue: § Licensed for the treatment of methaemoglobinaemia. § has tendency to make patients a bit blue. **these drugs try to target underlying pathophysiology - but none seem to work. Does this mean the hypotheses for AD are incorrect?

Second generation antipsychotics used in treatment of Schizophrenia (2+3/3)

2) Risperidone: o Very potent antagonist of 5-HT2A & D2 receptors. **Side effects: o More EPS & hyperprolactinaemia than other atypical antipsychotics. 3) Quetiapine: o Very potent antagonist of H1 receptors. **Side effects •Lower incidence of EPS than other antipsychotics.

What are the current drugs used for AD?

4 Current drugs: 1) Anticholinesterases: •Donepezil, rivastigmine & galantamine 2) NMDA receptor blocker: •Memantine: moderate/ severe AD

Muscarinic effects: eye

3 main effects: 1) •Contraction of the ciliary muscle: accommodation for near vision (lens becomes more convex) 2) Contraction of the sphincter pupillae (circular muscle of the iris): Constricts pupil (miosis) and improves drainage of intraocular fluid. ***IMPORTANT in glaucoma: Glaucoma - Contraction of sphincter pupillae opens pathway for aqueous humour, allowing drainage via the canals of Schlemm and reducing intra-ocular pressure. 3) Lacrimation (tears) § Glaucoma: 1. Contraction of the sphincter pupillae opens a pathway for aqueous humour, allowing drainage via the Canals of Schlemm thus reducing IOP - in glaucoma this is impeded.

What are the 4 types of receptor families

4 types based on: Þ Molecular structure Þ Signal transduction systems Type 1: Ion channel-linked receptors Þ Fast responses (m secs) Þ nAChR (excitatory causes sodium influx); GABAA (inhibitory, causes chloride influx) Type 2: G-protein-coupled receptors (7TM) Þ Slower responses (secs) Þ b1-adrenoceptors (heart) Type 3: Kinase-linked type Þ insulin/growth factors (mins) - most are tyrosine Type 4: Intracellular steroid type receptors Þ steroids/thyroid hormones (hrs) Þ regulate DNA transcription

Half-like of cannabis

7 days (lipid-soluble and enterohepatic recycling). onset is seconds --> minutes.

agonist

A chemical that mimics the action of a neurotransmitter. (ACh; nicotine)

Kidney physiology - countercurrent effect

A) o Descending limb - permeable to water. o Ascending limb - impermeable to water. B) o Na+ leaves the ascending limb and enters medullary Interstitium o Fluid in ascending limb decreases in osmolarity C) o More concentrated medullary interstitium draws water from the permeable descending limb o Fluid in descending limb increases in osmolarity D) o More fluid enters and forces fluid from descending to ascending limb - this fluid has increased in osmolarity due to increased Na+ concn in the medulla. E+F) o Na+ leaves the ascending limb and enters medullary Interstitium Fluid in ascending limb decreases in osmolarity. **Countercurrent important in reabsorbing water in collecting duct via aquaporins

Which of the following effects would be observed at rest after treatment with a ganglion blocking drug? A.Increased heart rate B.Pupil constriction C.Bronchodilation D.Detrusor contraction E.Increased gut motility

A.Increased heart rate; C.Bronchodilation. blocking parasympathetic.

How do muscarinic receptor agonists help to treat glaucoma? A.Increased ocular fluid drainage at trabecular meshwork B.Vasoconstriction of the vessels in the ciliary body C.Inhibition of carbonic anhydrase in the ciliary body

A.Increased ocular fluid drainage at trabecular meshwork

Bromocriptine is an M3 selective muscarinic agonist. Which of the following is the most suitable use for the drug? A.To aid bladder emptying B.Sedative C.To treat motion sickness D.To treat atropine poisoning E.Antiarrhythmic medication

A.To aid bladder emptying

Arrhythmias meaning

ABNORMAL OR IRREGULAR HEART BEATS. 350, 000 Deaths in US alone. Main cause - Myocardial Ischemia. o An increase in SNS drive to the heart via b1 can precipitate or aggravate arrhythmias, particularly after MI there is an increase in sympathetic tone. •AV conductance is also dependant on SNS activity as the refractory period is increased by b-adrenoceptor antagonists. o USE PROPANOLOL- non-selective b-antagonist class II drug: § Reduces mortality of patients with an MI. § Partially successful in arrhythmias that occur during exercise or mental stress.

ACEi hypertension treatment

ACE Inhibitors (ACEi) E.G. Enalapril (-PRIL ending for ACEi). § Renin-Angiotensin-System (RAS) stimulated by: a) LOW renal Na+ reabsorption. b) LOW renal perfusion pressure. c) HIGH SNS activation. § ACEi: a)Inhibit the somatic form of angiotensin converting enzyme (ACE) b) Prevent the conversion of angiotensin I to angiotensin II by ACE c) increase Bradykinin. *ATII actions: - SNS activation/thirst - vasoconstriction - salt and water retention - aldosterone secretion § Uses: o Hypertension. o Heart failure. o Post MI. o Diabetic nephropathy. o Progressive renal insufficiency. o High CVS-disease-risk patients.

Indications of antiplatelets

ARTERIAL THROMBI

What is affinity and efficacy and how is that related to potency?

Affinity is the ability of the molecule to bind to the receptor site. Efficacy is how much of an effect the drug will have once bound to the biological system. Potency = affinity + efficacy.

How does alcohol depress CNS?

Alcohol depresses the system by: 1) Increasing inhibition - pre- and post-synaptic. o pre-synaptically: alcohol increase release of allopregnenolone (neuroactive steroid) that then binds to GABA receptor and increases chloride influx. o post-synaptically: binds to and has positive effect on GABA receptor --> chloride influx. 2) Reducing excitation - reducing stimulation at NMDA receptors and reducing Ca2+ influx so less NT exocytosis. ** It's difficult to assess the acute CNS effects as CNS is a functionally COMPLEX system and ethanol has a low POTENCY (therefore low selectivity).

All adrenoceptors can be activated by __ and __?

All adrenoceptors can be activated by NA and A: •Selectivity for Noradrenaline a1 = a2 > b1 = b2 •Selectivity for Adrenaline b1 = b2 > a1 = a2 *** ALL -adrenoceptors are G-protein coupled o α1-receptors act through the phospholipase C system; triggering reactions to increase inositol triphosphate and diacylglycerol in the cell (IP3 and DAG). o α2-receptors act to decrease levels of cyclic AMP via the adenylyl cyclase system - they are regulators of release. o β-receptors result in an increase in cyclic AMP via the adenylyl cyclase system.

Alpha 1 vs Alpha 2 receptors

Alpha 1 receptors are the classic postsynaptic alpha receptors and are found on vascular smooth muscle. They determine both arteriolar resistance and venous capacitance, and thus BP. Alpha 2 receptors are found both in the brain and in the periphery. In the brain stem, they modulate sympathetic outflow

Nicotinic receptor antagonist aka

Also called ganglion blocking drugs. in both parasympathetic and sympathetic. they can either block NAch receptor (classic antagonist) or can be channel blockers. **Ganglion Blocking Drugs (GBDs): Properties: § GBDs can act to both antagonise the receptor AND/OR physically block the ion-channel itself. § Use-dependant blocks - the drug works best when the channel is open so the more the receptor is used, the more it is blocked. o Opposite to most with the more agonist meaning the less effective the drug is. § Incomplete blocking - Ion-channel blockade is only partial (as some ions still pass through). § Some GBDs do NOT have affinity as some types DON'T bind to the receptor, just block the ion-channel itself.

antibiotic resistance mechanism 3 - Altering target

Alterations in target enzymes: •Alteration to the enzyme targeted by the drug. Enzyme still effective but drug now ineffective **Example •S Aureus - Mutations in the ParC region of topoisomerase IV confers resistance to quinolones.

What is an opiate?

An alkaloid derived from the poppy, Papaver somniferum. These include the phenanthrene derivatives morphine and codeine. Opioids are compounds that act like morphine but which do not resemble morphine chemically, e.g. endogenous opioid peptides *history: o used in caves before death o used in egypt to stop the child crying o western europe - mixture of alcohol and morphine to get past alcohol regulation, v addictive o 1898 - made a safer one

Summary of drugs affecting heart rate, contractility and supply and demand

Angina treatment - angina is a classic mismatch between myocardial supply and demand: § b-blocker or CCA - background treatment. o Ivabradine - new more specific treatment. § Nitrate - symptomatic treatment (i.e. exercise). § Other - e.g. K-channel openers if intolerant to other drugs.

Morphine is always given intravenously. True or false?

False

Why use more than Antibiotic type when treating ulcers?

Antibiotics - more than one type as there is some small resistance.

What other endogenous mediators may contribute to the bronchoconstriction observed in patients with asthma?

Apart from histamine, Prostanoids, leukotrienes, bradykinin are examples covered elsewhere in the curriculum. o Prostanoids, leukotrienes, bradykinin are examples covered elsewhere in the curriculum.

Use of cholinomimetic drug in glaucoma

Aqueous humour produced by ciliary body, flows into anterior compartment to bathe lens and eye, then drains out into canals of schlemm in margin of iris into venous system. In glaucoma sometimes, the iris can become folded and reduces angle of drainage and rate of drainage is reduced and hence increase IOP --> damage retina/optic nerve. Can give cholinomimetic drugs to stimulate muscarinic receptors in circular muscles to return iris to normal position to open up channel for drainage in canals of schlemm.

Kidney Physiology - Loop of Henle - Countercurrent Effect:

Ascending limb is IMPERMEABLE to water but permeable to ions. Descending limb is PERMEABLE to water and NOT ions. 1. Loop is filled with isotonic fluid. 2. Na+ is pumped out of the ascending limb into the interstitium. Fluid in ascending limb decreases in osmolarity. 3. Concentrated interstitium pulls water into it from descending limb. Fluid in descending limb increases in osmolarity. 4. More fluid flows into the tubule and shifts the descending limb fluid into the ascending limb. 5. Na+ is pumped again out of the ascending limb into the interstitium. Ascending limb fluid decrease in osmolarity. 6. Na+ is pumped again out of the ascending limb into the interstitium. Ascending limb fluid decrease in osmolarity.

When would it be appropriate to take soluble aspirin and why would this formulation be advantageous over the others?

Aspirin is a very useful antiinflammatoryand anti-pyretic drug, which is available in a number of dosage forms: a) aspirin tablets B.P. - ordinary aspirin tablets sold in chemists b) soluble aspirin - these are dissolved in water and the solution swallowed c) enteric-coated aspirin - these have a sugar and wax coating which remains intact in dilute acid but quickly dissolves in alkali - stomach disease or if it is readily hydrolysed in stomach so want to keep drug intact

Aspirin would have limited effect on DVTs during long-haul flights why?

Aspirin would have limited effect on DVTs during long-haul flights as it treats arterial thrombi!

The figure below shows the response associated with a 10mg/kg dose of drug A (represents the ED50 for drug A). If you repeated this dose of drug A in the presence of a fixed dose of the relevant competitive receptor antagonist, where would you expect the "x" to be placed on the graph above in comparison to its current position? A. Directly above B. Directly below C. Shifted to the left D Shifted to the right E Superimposed

B. Directly below

How do muscarinic receptor antagonists influence function within the striatum and thus improve the symptoms of Parkinson's? A. Reduced GABA receptor activation B. Increased dopamine receptor activation C. Inhibition of DOPA decarboxylase D. Increased monoamine reuptake transporter function E. Increased dopamine secretion from nigrostriatal neurones

B. Increased dopamine receptor activation

Anticholinesterase drugs have the ability to increase activity at which synapses within the autonomic nervous system? A: All autonomic synapses B: Pre- and post-ganglionic parasympathetic synapses C: Pre- and post-ganglionic sympathetic synapses D: Post-ganglionic parasympathetic synapses only E: Pre-ganglionic sympathetic synapses only

B: Pre- and post-ganglionic parasympathetic synapses

Anticholinesterase drugs can be used to treat which of the following conditions? A: Asthma B: Glaucoma C: Hypotension D: Motion Sickness E: Peptic Ulcer Disease

B: Glaucoma

Morphine is used mainly for the control of mild to moderate pain. True or false?

False

Arterioles - Contribution to Blood Pressure

BP = CO x TPR § Arterioles contribute the greatest to blood pressure regulation. o more they contract --> less radius (r) for blood to flow--> increased resistance (R) --> decreased blood flow (F) to that tissue. o These vessels exhibit "vascular tone" and so always display a partial state of constriction. o Hypertensive patients tend to have a raised base vascular tone --> more TPR --> more B

BZs and BARBs on GABAA RECEPTOR COMPLEX

BZs & BARBs (benzodiazepines and barbiturates):- I) NO ACTIVITY ALONE (ALLOSTERIC ACTION; pams - positive allosteric modulator) 2) different binding sites from GABAAR and different mechanisms: Ø bzs increase FREQUENCY of opening of chloride channels Ø Barbs increase DURATION OF chloride channel opening. *both result in hyperpolarisation. 3) Barbs LESS SELECTIVE THAN bzs: § barbiturates also cause decreased EXCITATORY TRANSMISSION (inhibit glutamate mediated responses) § barbiturates also have other membrane effects (e.g. direct effect of chloride channel by barbiturates) *this may explain barbiturates: Ø induction of surgical anaesthesia Ø Low margin of safety (small therapeutic window)

Explain why beta-1 selective antagonists are effective treatments for hypertension and glaucoma.

Beta 1 receptors on the heart are found on cardiac nodal tissue, the conducting system, and contracting myocytes. They are responsible for enhancing pacemaker currents in the sinoatrial node and thus increasing heart rate and also increasing calcium entry to cardiac myocytes and this increasing contractility. The combined effect is to increase cardiac output and therefore increase blood pressure. This is why blockade of these receptors is a useful treatment for hypertension. The use of beta-1 selective antagonists to treat glaucoma is based on the ability to block beta 1 receptors in the ciliary body that are positively coupled to carbonic anhydrase. Carbonic anhydrase generates bicarbonate ions that are one component of aqueous humour. A build up of aqueous humour contributes to the generation of glaucoma, thus blocking beta 1 receptors is associated with a reduction in aqueous humour formation.

Opioid drugs act via intracellular receptors. True/ False

False

On the same night, an 18-year-old boy smokes several cannabis cigarettes in addition to drinking half a bottle of vodka. Over the course of the night, his motor skills deteriorate and he is eventually helped home to bed by a couple of friends. § Can you explain why the boy's motor skills have deteriorated?

Both of these drugs can act as depressants. Cannabis acts on cannabinoid receptors which are G protein coupled (Gi/o) and negatively regulate adenylate cyclase which leads to a decrease in cell activity. It is less clear which targets alcohol can influence, but it is known that the motor cortex is particularly sensitive to the effects of alcohol and most of the known targets for alcohol are related to decreased cellular activity (i.e. enhanced GABA or decreased calcium entry).

Opioid drugs normally excite their targets. True/ False

False

Protease inhibitors prevent viral attachment and entry. True/ False

False

A 48-year-old man was treated with oral betaxolol (beta-1 selective antagonist) to help treat his high blood pressure (155/90). A 64-year-old woman was treated with betaxolol eye drops to help treat glaucoma. Both patients had previously suffered with asthma and the man found that his betaxolol pills exacerbated his asthma whereas the woman had no such problems with her current anti-glaucoma medication, although previous treatment with timolol (non-selective beta antagonist) eye drops had worsened her asthma. § What does the ability of betaxolol to exacerbate asthma suggest about the selectivity of this drug?

Bronchodilation is a beta 2 receptor mediated event. The fact that betaxolol is a beta 1 selective antagonist suggests that it is more selective for beta 1 than for beta 2 (about 10 fold more affinity for beta 1 than beta 2) - this does not mean that it has no activity at beta 2 receptors. The fact that it has some activity at beta 2 receptors explains why an asthmatic individual might develop some degree of bronchospasm after oral treatment with betaxolol.

•Which of the following statements is most accurate? A: A partial agonist will always have a higher efficacy than a full agonist B: Agonists have higher affinities than antagonists C: Full agonists that are selective for a given receptor will have the same efficacy D: Antagonists possess better efficacy than their respective agonists E: Competitive antagonists will preferentially occupy the relevant receptor in the presence of agonist

C

Regarding ethanol metabolism: Disulfiram enhances ethanol metabolism. True/ False

False

The low-molecular weight heparins are classed as anti-platelet drugs. True/ False

False

Thiazides exert diuretic effects which are due mainly to blockade of carbonic anhydrase. True or False?

False

Which of the following effects would be observed after blockade of nicotinic acetylcholine receptors in an individual at rest? A.Bronchoconstriction B.Increased sweat production C.Constipation D.Increased urinary frequency E.Short-sightedness

C.Constipation

Benzodiazepines are used to treat 'panic attacks' and other anxiety states. By what mechanism do they produce their anti-anxiety effects? A: Inhibition of GABA breakdown B: Activation of 5HT1A receptors C: Enhancement of the action of GABA at GABA-A receptors D: Inhibition of GABA reuptake E: Enhancement of the action of GABA at GABA-B receptors

C: Enhancement of the action of GABA at GABA-A receptors

The 'cheese reaction' is most likely to be caused by: A: Tricyclic antidepressants (TCAs) B: Selective serotonin reuptake inhibitors (SSRIs) C: Monoamine oxidase inhibitors (MAOIs) D: Reversible MAO-A inhibitors (RIMAs) E: α2-Adrenoceptor antagonists

C: Monoamine oxidase inhibitors (MAOIs)

NSAIDS inhibit which enzyme

COX (COX 1 and 2 are the rate limiting steps for prostanoid production). § Two isoforms of COX (COX1 and COX2) and NSAIDs inhibit BOTH to varying degrees (e.g. ibuprofen). § Coxib family - selectively reversibly inhibits COX2 (e.g. celecoxib

Different classes of fungal infections

Can be classified in terms of tissue/organs: 1.Superficial - Outermost layers of skin 2.Dermatophyte - Skin, hair or nails 3.Subcutaneous - Innermost skin layers 4.Systemic - Primarily respiratory tract

Principal sites of opiate/opioid action in the pain pathways

Cellular Mechanism of Action: § Located mainly in the CNS but also found in the periphery § Depressant effect § Hyperpolarisation ( K+) § ↓ Ca2+ inward current

Alcohol Acute effects: CVS HR

Centrally mediated decrease in baroreceptor sensitivity leads to an acute increase in heart rate and chronic alcohol may be associated with an increased blood pressure. o Alcohol diminishes the control of the brain on the arterial baroreceptors and so the heart receives less inhibitory input. o SNS becomes dominant and heart rate increases.

Thrombolytics (fibrinolytics) are primarily used for the treatment of deep vein thrombosis. True/ False

False

•A 4 year old girl is bitten by a Tiger snake whilst holidaying in Australia. An anti-venom (harvested antibodies) is administered. Which form of antagonism is utilised by the anti-venom? A: Competitive receptor blockade B: Physiological antagonism C: Chemical antagonism D: Pharmacokinetic antagonism E: Irreversible receptor blockade

Chemical antagonism

Cocaine - Pharmacodynamics:

Cocaine - Pharmacodynamics: 1) Local anaesthetic - high-dose cocaine: o Cocaine (+ve charged) can block the sodium channels to cause a local anaesthetic effect - inhibits conduction of AP. 2) Re-uptake inhibition - low-dose cocaine: o MAO-A re-uptake inhibitor (uptake 1). o This can affect re-uptake of - NA, DA, 5-HT. o Note - this is not changing the affinity or efficacy dopamine, just increasing the DA in the synaptic cleft. 3) Euphoria: o Reduces re-uptake of DA into pre-synaptic neurone so more DA in the NAcc (from the VTA). 4) o Acute-use - mild-moderate effects: § There are initially positively reinforcing effects such as mood amplification and heightened energy but this flips to... 5) Chronic use - severe effects: § Chronic higher-dose users tend to then to start to exhibit severe effects such as total insomnia and decreased libido. 6) Cardiovascular (MI): o Increased catecholamines and increased sympathetic drive on the heart increases oxygen demand on the heart. o Vasoconstriction decreases delivery of oxygen to the heart. o Result is ischaemia of the heart muscle. 7) CNS: o Vasoconstriction. o Hyper-pyrexia (fever) --> epilepsy.

•A drug acting as an inhibitor at a particular drug target site prevents the removal of neurotransmitter from the synapse. Which type of drug target is this drug acting on? • A: Receptor B: Voltage-sensitive ion channel C: Receptor-linked ion channel D: Transport protein E: Non-proteinaceous target

D

Which one of the following drugs would you use to treat a pulmonary embolism? a) aspirin b) clopidogrel c) alteplase d) dalteparin e) abciximab

D -‐dalteparin -‐this is a low MW heparin, the rest of the drugs are antiplatelets *Other questions 1) C -‐damage to the tunica intima. 2) B -‐heparin -‐it enhances the action of antithrombin (AT-‐III), which inhibits factors 2a and 10a. Remember the effects of warfarin take a little while to be seen. 4) E -‐alteplase -‐clot busters have a very high risk of bleeding

Valproate is another anticonvulsant with the same mechanism of action as carbamazepine. True/ False

False

Warfarin activity is monitored by means of APTT. True/ False

False

Warfarin inhibits factors III, V, VII & XI. True/ False

False

Warfarin is administered intravenously. True/ False

False

Warfarin is used in the treatment of acute MI. True/ False

False

The figure below shows a Phase 1 metabolic reaction. What type of Phase 1 reaction has taken place in this figure? A. Acetylation B. Hydrolysis C. Oxidation D. Reduction E. Sulphation

D. Reduction. There is extra NH2 groups. For hydrolysis - would expect to see some OH groups

Inflammation in atherosclerosis is important only in the early stages of the disease. True or False?

False - Inflammation is involved in all stages of atherosclerosis

Describe the underlying pathology thought to be responsible for the motor-symptoms of PD

Degeneration of the dopaminergic pathway from the substantia nigra to the striatum. Known as the nigrostriatal pathway.

What would you predict that prior administration of a muscarinic antagonist would do to the position of this semi-log plot and why?

Depending on the relative concentrations and change in resistance we are looking for, it should prevent the increase in resistance since it would physically occupy the muscarinic receptors and hence block the constrictor actions of acetylcholine on the airway smooth muscle. If we gave a high enough dose of metacholine, we could overcome the blockade but clinically, we have no clinical reason for making it harder for someone to breath.

A 20-year-old male visits his GP with persistent apprehensive feelings about upcoming events. He reports that for the last 3-months he cannot concentrate on his work because he is worried about failing his upcoming exams and he has been having difficulty sleeping for the last 4 weeks. The GP conducts a series of tests and subsequently refers the patient to a psychoeducational group. In a follow-up appointment the GP diagnoses the patient with generalized anxiety disorder (GAD). Despite the UK guidelines for GAD management the GP prescribes a benzodiazepine. § Consider the table below and suggest which benzodiazepine would most likely be prescribed and why.

Diazepam is the drug of choice since it has a rapid onset of action and the slow elimination protects against major fluctuations in blood concentrations.

Inflammation in atherosclerosis mainly involves neutrophils. True or False?

False - The main inflammatory cell type involved in atherosclerosis is the macrophage, which is converted to a foam cell

Cocaine can induce miosis (pin point pupil). True/ False

False

Cocaine can only be administered by the intravenous route. True/ False

False

Concerning Parkinson's disease: Deprenyl (selegiline) is a selective mono- amine oxidase-A (MAO-A) inhibitor. True/ False

False

Dihydropyridine calcium channel blockers cause swollen ankles. True/ False

False

Dihydropyridine calcium channel blockers inhibit calcium entry via the sodium calcium exchanger. True/ False

False

Dihydropyridine calcium channel blockers prolong bleeding time. True/ False

False

Dihydropyridine calcium channel blockers slow heart rate. True/ False

False

Drugs that target the chemokine CCR5 receptor are effective in the treatment of HIV. True/ False

False

Ethanol has an anti-diuretic effect. True/ False

False

Increased parasympathetic activity in the cardiovascular system decreases beat to beat variability. True/ False

False

Increased parasympathetic activity in the cardiovascular system increases heart rate. True/ False

False

Increased parasympathetic activity in the cardiovascular system may occur during fainting (syncope). True/ False

False

Inflammation in atherosclerosis may be suppressed by statins and fibrates. True or False?

False

Morphine acts only on κ opioid receptors. True or false?

False

Methyldopa

False transmitter. Instead of NA get alphamethylNA. This means that it will behave like NA but is not very good for beta/a1 and is more selective for a2 and hence more of a negative feedback effect. is not metabolised by MAO - so remains in synapse and no conc gradient so uptake is less and gets more binding to a2 and further inhibition of NA release. Improved blood flow!! Anti-hypertensive, especially; Renal - kidney disease; CNS - cerebrovascular disease

Both heroin and fentanyl are opioid agonists, so how is it that, in this case, one causes euphoria and the other unconsciousness and respiratory depression? What would you expect the fentanyl and heroin dose-response curves to look like?

Fentanyl is much more potent and shifts the dose-response relationship to the left and thus a much smaller dose is required to produce a euphoric effect. different routes - fentanyl goes through medulla (respiratory centre), heroin goes nucleus accumbens. fentanyl is higher, requires less to get same response

What does D-dimer test detects?

Fibrin degradation products

What are the five main classes of diuretics?

Five main classes - different mechanism of action: 1. Osmotic diuretics - e.g. mannitol - increases osmolality of tubular fluid so prevents water leaving 2. Carbonic anhydrase inhibitors e.g. acetazolamide - act in PCT 3. Loop diuretics e.g. frusemide (furosemide) - ascending limb 4. Thiazides e.g. bendrofluazide (bendroflumethiazide) - distal tubule 5. Potassium sparing diuretics e.g. amiloride, spironolactone - late DCT and CD.

What kind of illness could affect the bioavailability of drugs?

GIT diseases, liver disease, diseases affecting blood flow

Describe the mechanism of action of haloperidol

Haloperidol is primarily a dopamine D2-receptor antagonist and falls into the category of drugs known as first-generation antipsychotics (FGAs) or aka typical neuroleptics. § NB: QD means once daily

What are the main pharmacokinetic properties of anticonvulsant drugs? They are able to bypass first-pass metabolism/ Can be delivered as a patch formulation/ Have a fast onset and long duration of action/ They do not interact with other drugs/ They are excreted via the kidneys.

Have a fast onset and long duration of action

Does heroin or alcohol have greater selectivity?

Heroin - it has more functional groups and is generally more complex and thus has a greater selectivity to its receptor (this also means it would produce less side effects)

Two examples of nicotinic receptor antagonists

Hexamethonium (receptor blocker) & Trimetaphan (ion channel blocker). use-dependent block for ion channel - more open the channels are; the more effective the drug antagonist is. is an incomplete block, as never get a complete block of ion channel. as blocks all autonomic ganglia, the main effect depends on whether sympathetic or parasympathetic was dominant at the time.

What is a hypnotic?

Hypnotics: induce sleep *Ideally: they should: I) have wide margin of safety Ii) Not depress respiration Iii) Produce natural sleep (hypnotics) Iv) Not interact with other drugs V) not produce 'hangovers' Vi) Not produce dependence. **these drugs in pic can have overlapping effects when vary the drug doses

• Why is it important to understand the effect that enzymes have on a given drug?

Improve drug efficacy and limit drug toxicity

Methyldopa clinical use

Improved blood flow!! Anti-hypertensive, especially; Renal - kidney disease; CNS - cerebrovascular disease

Neuromuscular blockade by tubocurarine is used as an adjunct to anaesthesia in surgery. How does tubocurarine bring about its effects at the motor end plate? Inhibition of acetylcholine release from nerve endings/ Antagonism of the actions of acetylcholine at nicotinic receptors/ Causes persistent depolarisation/ Increases the rate of acetylcholine breakdown/ Prevents opening of the voltage sensitive Na+ channels.

Inhibition of acetylcholine release from nerve endings

Examples of indirectly acting cholinomimetic drugs

Inhibitors of Cholinesterase enzymes. 1) Reversible anticholinesterases: Physostigmine, neostigmine, donepezil. § They donate a carbamyl group to the enzyme active site, blocking the active site (competitive). § The carbamyl group is then removed via SLOW hydrolysis (minutes). § Physostigmine - a tertiary amine, acts at the postganglionic PNS synapse. o Used to treat glaucoma (aids IOP reduction). o Used to treat atropine poisoning. 2) Irreversible anticholinesterases: Ecothiopate, dyflos, sarin (all organophosphate compounds): § Rapidly react to enzyme active site and leave a large blocking group - stable and resistant to hydrolysis. § Ecothiopate - a potent inhibitor of acetylcholinesterases. o Slow reactivation of the enzyme takes several days. o Used to treat glaucoma (eye drops) with a prolonged duration of action. o Side effects - sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty.

Type 3 of drug antagonism: Chemical antagonism

Interaction of drugs in solution (as opposed to binding to specific receptors). I.E. If people have heavy metal poisoning, you give dimercaprol to bind the heavy metal and form non-toxic clumps which can be excreted (before they get absorbed). so: dimercaprol --> heavy metal complexes (chelating agent)

Isoprenaline summary

It is based on the structure of adrenaline, but the slight difference means that it is less susceptible to metabolism by MAO and because of this, it has a longer plasma half-life (2 hours) **-Clinical Uses: oCardiogenic Shock oAcute Heart Failure oMyocardial Infarction **-Historically it was used to treat asthma due to actions on β2-adrenoceptors, but the cardiovascular effects (vascular smooth muscle relaxation in blood vessels in the muscles causing a drop in BP) of isoprenaline meant this often resulted in fatal reflex tachycardia or dysrhythmias and is now therefore discontinued for this purpose -BE CAREFUL OF THIS

How are lipids carried in circulation

Lipoproteins: HDL useful (marked by apoprotein A1) and LDL for atherosclerosis (apoprotein B). § The apoproteins define the type of lipoprotein: o A-1 - HDL. o B - LDL. § Exogenous pathway - when we eat food, it is broken down into chylomicrons (large) which are further broken down into FFAs and chylomicron remnants. o Chylomicron remnants --> deposit in vessels --> atheroma.

The antagonism produced by losartan (Angiotensin II receptor blocker) is regarded as 'surmountable' whereas the antagonism produced by candesartan (Angiotensin II receptor blocker) is regarded as 'insurmountable'. What do you understand by this? How might this explain the GP's decision to switch medication?

Losartan is a competitive receptor antagonist. It competes with angiotensin II for the angiotensin receptor. It can only bind to the receptor for a matter of seconds, and is therefore constantly unbinding from the receptor and leaving it available for agonist binding. Candesartan is an irreversible receptor antagonist. It binds strongly to the angiotensin receptor and as a result does not need to 'compete' with angiotensin for the receptor (in reality, candesartan remains bound to the receptor for approx 2 hour).The fact that candesartan blockade of the angiotensin receptor is longer lasting than that seen with losartan certainly suggests that the duration of action is longer for candesartan. As a result, the GP may suggest switching to candesartan to ensure better 24 hour blood pressure control. The fact that this patient has responded well to this class of drugs in the past would certainly support the use of another drug from the same class.

A section of guinea pig ileum is placed in an organ bath and stimulated with increasing doses of methadone (opioid receptor full agonist). Following removal of methadone, the same tissue is stimulated with buprenorphine (opioid receptor partial agonist). What would you expect the dose-response curve of buprenorphine to look like compared to methadone? NB: Vmax = maximum effect, ED50 = dose at which half the maximum effect is achieved. Same Vmax & same ED50/ Higher Vmax & higher ED50/ Lower Vmax & same ED50/ Lower Vmax & lower ED50/ Same Vmax and lower ED50.

Lower Vmax & same ED50

What side effects might Mr MacKenzie experience after treatment with an oral muscarinic antagonist?

Main ANS effects: tachycardia, relaxation of smooth muscle (gut, bronchi, biliary tract, bladder) inhibition of secretions (salivary, lacrimal, bronchial, sweat, gastric acid) Main CNS effects: depends on drug - atropine is excitatory, hyoscine causes sedation in low doses. Anti-emetic, anti-extrapyramidal and so useful in Parkinson's disease)

What is an excipient?

Medicines are the dosage forms used, which contain the drug in question and also include a number of other materials called EXCIPIENTS. These excipients may be added to aid the manufacture of the medicine, to improve its chemical and biological stability or to increase its acceptability to the patient by improving its flavour, fragrance or appearance. The process of making a medicine containing a drug is called FORMULATION and is an important part of the development process in the pharmaceutical industry.

What type of receptors does ACh activate?

Muscarinic (Subdivided into classes 1-3) and nicotinic (subdivided into two classes - ganglionic and NMJ)

What are the two receptors for ACh?

Muscarinic or Nicotinic

Blockade of which of the following receptor sub-types would induce both an increased heart rate and a reduction in sweat production during exercise? A.Muscarinic receptors B.α1 adrenoceptors C.α2 adrenoceptors D.β1 adrenoceptors E.β2 adrenoceptors

Muscarinic receptors

SNS transmitters/ receptors

NA produced from tyrosine, into vesicles, exocytosis and Ca2+ influx release NA into synapse, onto A1 receptor activated, a2 receptor receptor mediated negative feedback on pre-synaptic response. prevents further release of NA and is tightly regulated and switched off quickly.

Sub-types of muscarinic cholinoceptors

NCEPS. o M1 - Neural (Forebrain - learning & memory) o M2 - Cardiac (Brain - inhibitory autoreceptors) o M3 - Exocrine & smooth muscle (Hypothalamus - food intake) o M4 - Periphery: prejunctional nerve endings (inhibitory) o M5 - Striatal dopamine release

Phentolamine summary

NON-SELECTIVE Alpha antagonist. •Phentolamine was the first non-selective α-antagonist •The blockade of α1-receptors leads to vasodilation and a fall in total peripheral resistance and blood pressure •Used to treat phaeochromocytoma induced hypertension. *•Pheochromocytoma (PCC) is a neuroendocrine tumor of the medulla of the adrenal glands (originating in the chromaffin cells), or extra-adrenal chromaffin tissue that failed to involute after birth, that secretes high amounts of catecholamines.* •Why do alpha 2 receptors and baroreceptors reduce the effectiveness of phentolamine? •Unwanted effects - mainly mediated by α2-receptors and barorecptors •The blockade of a α2-receptors leads to a loss of inhibition of noradrenaline release from presynaptic nerve terminals, thereby increasing NA release and causing enhanced reflex tachycardia.

Viral hepatitis - types, tropism and treatment

O Hepatitis infection results in inflammation of the liver cells (hepatocytes). There are five characterised hepatitis viruses named hepatitis A virus (HAV), HBV, HCV, HDV and HEV. HAV and HEV infection result in very similar symptoms and can be controlled by good hygiene and sanitation. HDV is a 'sub-viral satellite' agent meaning that it requires another virus (in this case HBV) to assemble and infect new cells. O HBV is transmitted via exposure to infected blood or bodily fluids and infects the hepatocytes of the liver. Although around 95% of adults spontaneously recover from the illness, chronic infectioncan lead to life threatening complications such as cirrhosis. Chronic HBV can be treated with the nucleoside RT inhibitor Lamivudine but initial treatment with pegylated interferon (peginterferon) alpha 2a is recommended. O HCV is spread through blood contact (mainly infected needles or blood transfusions) and affects the hepatocytes of the kidney. The majority of individuals who are acutely infected become chronically infected, which can lead to advanced liver disease and hepatocellular carcinoma. The standard therapy for chronic HCV is a combination of peginterferon alpha & the nucleoside analogue ribavirin. However, this therapy is only effective in around 50% of patients. The protease inhibitor, boceprevir is also licensed for the treatment of chronic hepatitis C in combination with the two aforementioned drugs. § Tropism: •Liver hepatocytes § Hepatitis (Hep) B & C: •Only chronic infection requires treatment § Hep B treatment (DNA virus): •Tenofovir --> nucleotide analogue (blocks viral DNA replication), given sometimes with Peginterferon alfa. Tenofovir is also used to treat HIV. DOES NOT CURE; but maintains undetectable level of viral DNA (in case of Hep B) and viral RNA (in the case of HIV). As soon as stop tenofovir, Hep B comes back; so turns disease into manageable state but does not cure. § Hep C treatment (RNA virus): a) Ribavirin & Peginterferon alfa •Ribavirin --> nucleoside analogue prevents viral RNA synthesis b) Boceprevir --> protease inhibitor •Most effective against Hep C genotype 1

Thinking about drugs in general, why might the dose of a drug taken by a patient differ from that prescribed by his or her physician?

O Mistake in prescription by doctor. O Mistake in dispensing prescription by pharmacist. O Misunderstanding of dosing instructions by patient ( e.g believing that taking 3 pills all at once, the same as taking one pill three times a day). O Non-compliance by patient (e.g. because of fears of side effects [esp with glucococorticoids], as a result of confused or depressed mental state). O Also, patient may take correct dose, but it may not be absorbed due to interaction with food in stomach e.g. bisphosphonates (used to stabilise/build bone in patients with osteoporosis) which are chelated by calcium, magnesium and iron, so are not absorbed if taken with food or milky drinks.

Presentation and investigations during DVT

O Presentation: •Immobile for 3 weeks after major surgery •Right calf swollen & collateral superficial veins present •Palpation - localised tenderness & pitting oedema. O Investigations: •Blood pressure = 112/73, Pulse rate = 68 bpm, Respiratory rate = 12 breaths per minute, SpO2 = 98% •Two-level Wells score = 5. Blood taken for D-dimer testing & proximal leg vein scan is arranged

What is bioequivalence?

Once the patent on a new drug has expired, it is possible for any drug company to manufacture and market the drug. This often means that cheaper examples (GENERIC VERSIONS) of the same drug can be made, in which the formulation is slightly different. However, not all formulations will be equivalent and this can dramatically alter the bioavailability of the drug. Thus, regulatory authorities lay importance on evidence of BIOEQUIVALENCE, that is, evidence that the new 'generic' product behaves sufficiently similar to the existing one to be substituted for it without causing clinical problems. This is particularly important when a drug has a narrow (small) THERAPEUTIC INDEX (or THERAPEUTIC WINDOW).

MUSCARINIC RECEPTOR ANTAGONISTS - Clinical Use in ophthalmology

Ophthalmic - pupil dilates - used to exam back of the eye for retina examination

What are the possible treatments for reducing intraocular pressure?

Options are: a) Alpha agonists - decreases production of fluid and improves drainage. b) Beta blockers - decrease production of aqueous humour - possible potential for bronchospasm. c) Carbonic anhydrase inhibitors - decrease production of aqueous humour. d) Muscarinic agonists - cause constriction of pupil and contraction of the ciliary muscle which opens up the trabecular meshwork and improves drainage -possible potential for bronchospasm. e) Prostaglandin analogues -increase drainage from eye - may cause changes in iris colour. Contrasting evidence for the effect on asthmatics. Some studies show that asthmatic symptoms reduced after discontinuance of PAs. **For diabetics/asthmatics should avoid: a) Beta blockers - possible potential for bronchospasm and can also be dangerous for diabetics. b) Muscarinic agonists - possible potential for bronchospasm. c) Prostaglandin analogues - Contrasting evidence for the effect on asthmatics. Some studies show that asthmatic symptoms reduced after discontinuance of PAs.

Other routes of drug excretion apart from kidney and liver

Other routes (usually of little quantitative importance)... lungs, skin, gastrointestinal secretions, saliva, sweat, milk, genital secretions

Strategies other than COX-2 selective NSAIDS for limiting GI side effects

Other than COX-2 selective NSAIDs: § Topical application - less systemic access. § Limit NSAID use in patients with a GI-ulceration history or with other risk factors (e.g. alcoholics). § Treat H. pylori if present. § Co-administer omeprazole (or another PPI). § Minimise NSAID use in patients with other risk factors and reduce risk factors where possible e.g. alcohol consumption, anticoagulant or glucocorticoid steroid use

PGE2 in inflammation

PGE2 role in Inflammation extremely complex... not going to consider isolated examples because they are not generalisable

Different types of response in sympathetic vs parasympathetic NS

PNS - discrete/ localised (little divergence, 1:1 pre- vs post), long pre-ganglionic neurone SNS - coordinated response (very divergent, up to 1:20 pre vs post), long post-ganglionic (ganglia in sympathetic trunk)

Spironolactone

POTASSIUM SPARING DIURETICS, E.G. SPIRONOLACTONE, AMILORIDE § Locus of action: distal tubule § Antagonists of aldosterone-sensitive Na+ channels: Mode of action: channel blockade. **Consequences: o Block of Na+/K+ exchange mechanism - increased Na+ and decreased K+ loss o Small increase in urine volume ** Clinical uses: With K+ losing diuretics to prevent K+ loss. Primary and secondary hyperkalaemia.

Pain in angina

Pain, that occurs when the oxygen supply to the myocardium is insufficient for its needs. Pain distribution - chest, arm , neck. Brought on by exertion or excitement.

Actions and MoA of paracetomal

Paracetamol NOT an NSAID as no anti-inflammatory action. § Actions: o Relieve mild --> moderate pain. o Anti-pyretic actions. o NO anti-inflammatory actions. § MoA: o Not understood but probably central. o COX3, cannabinoid receptors, interactions with endogenous-opioids/5HT/adenosine-receptors?

Pharmacodynamic Drug Interactions

Pharmacodynamics - drug's effects on the body - e.g. receptor site dynamics. § Additive, synergistic, or antagonistic effects from co-administration. o Synergistic actions of antibiotics - use of two ABs will increase the effect more than their separate contributions (i.e. 2+2=5) OR they antagonise each other. o Overlapping toxicity - ethanol and benzodiazepines (both are NS depressants). o Antagonistic effects - anticholinergic medications.-(amitriptyline and acetylcholinesterase inhibitors)

summary of phase 2 reactions and conjugating agents and target functional groups

Phase 2 reactions... § ...are all conjugation reactions using -OH, -NH2, -SH and -COOH. § ...include glucuronidation, sulphation, acetylation, methylation, conjugation with amino acids and with glutathione. § ...involve high energy intermediates such as UDPGA for glucuronidation or PAPS for sulphation.

Physiology of Hypertension

Physiology •Blood pressure (BP) = cardiac output (CO) x total peripheral resistance (TPR) The tissue targets for antihypertensive drugs are: 1) Sympathetic nerves (releases noradrenaline) - b1 / b2 2) Kidneys (regulates blood volume via the renin-angiotensin-aldosterone system) - b1 3) Heart (controls cardiac output; HR and Force of Contraction) - b1 4) Arterioles (determines peripheral vascular resistance) 5) CNS (determines blood pressure set point and regulates some systems involved in blood pressure control) - b1 / b2

Three examples of glucocorticoids used in IBD?

Prednisolone, Fluticasone, Budesonide

Pros and cons of Subcutaneous - into connective tissue spaces under skin

Pro: 1) Local administration, dissemination can be minimised for local effect 2) enables DEPOT THERAPY (as for intramuscular above) Con: 1) pain, abscess, tissue necrosis

Which one of the following drugs would you prescribe to an individual suffering from motion sickness? Promethazine (H1 receptor antagonist)/ Ondansetron (5-HT3A receptor antagonist)/ Arepepritant (neurokinin-1 receptor antagonist)/ Metoclopramide (Dopamine D2 receptor antagonist )/ Dexamethasone (glucocorticoid).

Promethazine (H1 receptor antagonist)

Pros and cons of drug inhalation - via lungs and respiratory tract

Pros: 1) ideal for small molecules, particles, gases, volatile liquids, aerosols 2) enormous surface area presented by alveolar membranes 3) simple diffusion, also phagocytic cells clear particles Cons: 1) possible localised effect within lung (unless this is desired)

With respect to the distribution of a drug around the body: Regional blood flow is an important factor/ The distribution profile of a drug is determined by its carbon content/ Capillary structure is unimportant/ If a drug is highly plasma-protein bound it is not free to be distributed from the blood stream/ Active transport into tissues does not influence this process.

Regional blood flow is an important factor/

What are the two types of indirectly acting cholinomimetic drugs?

Reversible and irreversible anticholinesterases. • INCREASE effect of NORMAL parasympathetic nerve stimulation • Reversible anticholinesterases: PHYSOSTIGMINE, neostigmine, donepezil ('Aricept') • Irreversible anticholinesterases: ECOTHIOPATE, dyflos, sarin

Prazosin summary

SELECTIVE Alpha-1antagonist. •This produces vasodilation and a fall in arterial pressure, but less reflex tachycardia (NO alpha 2 actions) *Clinical Uses: •Lowers BP •Reduces BPH symptoms •Modest decrease in LDL and increase in HDL levels

Which is more serious STEMI or NSTEMI?

STEMI as full occlusion of coronary artery

What is a sedative?

Sedatives: reduce mental and physical activity without producing loss of consciousness. *Ideally: they should: I) have wide margin of safety Ii) Not depress respiration Iii) Produce natural sleep (hypnotics) Iv) Not interact with other drugs V) not produce 'hangovers' Vi) Not produce dependence. **these drugs in pic can have overlapping effects when vary the drug doses

Thrombosis initial stages molecular level (3)

Small-scale thrombin production 1.Tissue factor (TF): •TF bearing cells activate factors X & V forming --> prothrombinase complex 2.Prothrombinase complex •This activates factor II (prothrombin) creating factor IIa (thrombin) 3.Antithrombin (AT-III) •AT-III --> inactivates fIIa & fXa

Why would you want a drug to be lipophilic?

So it can access tissues - therapeutic effect

Spironolactone utilises a different method to reach its site of action in the kidney compared to bendrofluazide/furosemide. How does it access its target?

Spironolactone is lipid soluble (rather like the endogenous agonist for the mineralocorticoid, aldosterone). As such, when it reaches the kidney it can diffuse across the glomerulus (apart from the proportion that is plasma protein bound) and more importantly, can diffuse across from the peritubular capillary into the tubular cell - no need for carrier mediated transport. Once in the cell, spironolactone will bind to the mineralocorticoid receptor and prevent it translocating to the nucleus.

Standard oral glucocorticoids vs budesonide at inducing remission in active CD

Standard oral glucocorticoids better than budesonide at inducing remission in active CD

Step 1 in treating hypertension

Step 1 - Single Therapy: § Under 55 - ACE or ARB (Angiotensin Receptor Blocker). o The reason those drugs are the first line drugs is due to the good patient adherence as seen in studies (left figure). o Higher adherence = less side effects. o Not much difference between ACEi and ARB in reducing BP. § Over 55, Afro-Caribbean - CCB or Thiazide diuretic. o This group of people have a different drug schedule due to low plasma renin activity and so ACEi doesn't work as well - the studies into this are not confirmed.

Which one of the following neurones is associated with noradrenaline neurosecretion? Preganglionic sympathetic neurone innervating the sympathetic trunk/ Postganglionic sympathetic neurone innervating the kidney/ Sympathetic neurone innervating the adrenal medulla/ Postganglionic parasympathetic neurone innervating the heart/ Postganglionic sympathetic neurone innervating the sweat glands.

Sympathetic neurone innervating the adrenal medulla

Bioavailability definition

The bioavailability of a drug is the amount of a drug contained in a medicine that enters the systemic circulation in an unchanged form after administration of the product. (Proportion of the administered drug that is available within the body to exert its pharmacological effect.)

Constituents of blood

The liquid component of blood is known as plasma and comprises around 55% of the total blood content. The remaining 45% is made of blood cells namely erythrocytes (red blood cells), leukocytes (white blood cells) and thrombocytes (platelets).

Describe how bendrofluazide/furosemide reach their site of action if they are administered orally (none of these drugs are freely filtered).

The drugs would need to be absorbed from the gastrointestinal tract. They would then enter the portal blood supply and be delivered to the liver (some first pass metabolism would occur. The drug would then drain from the liver into the venous system and be returned to the heart (right side to the pulmonary circulation/left side to the systemic circulation). Once in the systemic circulation, these drugs would eventually be delivered to the kidney. They could not be filtered at the glomerulus, so would pass onto the peritubular capillaries. It is important to note that these drugs need to get from the basolateral side of the tubule (i.e. the capillary) across the cell to the luminal side of the tubule (i.e. across the tubular cell). These drugs are transferred to the luminal side of the membrane by the relatively non-selective carrier proteins that transport a large number of drug molecules into the lumen for excretion. In this case, both drugs are weak acids so will be transported by the carrier system that transports acidic drugs. There is another for basic drugs. Once in the lumen, these drugs can access their respective drug targets which reside in the luminal membrane.

Why would you administer atropine to try to reverse the effects of the organophosphate?

The effects of the organosphosphate poisoning are due to the blockade of acetylcholinesterase and the build up of acetylcholine in the synapse, leading to an excessive stimulation of the muscarinic receptor. Atropine is a competitive receptor antagonist for the muscarinic receptor. If you administer a high dose of atropine it will compete with acetylcholine for the muscarinic receptor - at any given moment a significant number of atropine receptor complexes will be formed compared with acetylcholine receptor complexes and as a result the response to acetylcholine will be reduced.

What is the goal of HCV treatment today?

The goal of HCV treatment TODAY is to cure the virus. Cured in almost 100% of cases; only very complex cases are sometimes difficult to treat. *this is done with a combination of drugs. The specific drugs and the duration of treatment depend on: § HCV genotype (genetic structure of the virus) § viral load § past treatment experience § degree of liver damage § ability to tolerate the prescribed treatment § need for liver transplant **DAA - Directly Acting Antivirals: o There are structural and non-structural proteins we can directly target with drugs in production now.

Arthur Jones is a 72-year-old gentleman who has atrial fibrillation which could not be converted back to sinus rhythm. He has suffered a small stroke. It was decided to prescribe warfarin to prevent a recurrence. The dose is stabilised but he later develops a chest infection and is given clarithromycin for one week. This effectively treats the infection but he has a severe nosebleed and notices that he bruises very easily. Why? What other drugs might produce a similar effect?

The metabolism of warfarin, by the cytochrome P450 pathway, is inhibited by erythromycin leading to increased plasma levels of warfarin. Many other drugs may do this: § other antibiotics of the same class (macrolides) eg clarithromycin § some antibiotics of other classes such as quinolones like ciprofloxacin § systemic antifungal drugs eg fluconazole, itraconazole § proton pump inhibitors used for peptic ulcers eg omeprazole § some anti-HIV drugs esp protease inhibitors

What is a prostanoid?

The prostanoids are a family of lipid mediators generated by the action of cyclooxygenase on a 20-carbon unsaturated fatty acid, arachidonic acid. Prostanoids are a subclass of eicosanoids consisting of the prostaglandins (mediators of inflammatory and anaphylactic reactions), the thromboxanes (mediators of vasoconstriction), and the prostacyclins (active in the resolution phase of inflammation.

Describe what a semi-log plot showing the effect of an increasing dose of metacholine on airways resistance, would look like. How would you label the axes? draw a labelled semi-log plot.

The semi-log plot would have methacholine concentration on the x-axis and resistance on the y-axis. It would have a sigmoidal appearance. With metacholine would cause normal response of airway resistance with vagal activation to shift to right (competitive inhibitor).

Dronabinol, Nabilone

There is upregulation of CBRs in: o MS/pain/stroke patients - to regulate pain (protective effect) o Fertility/obesity - this is pathologic and may contribute to obesity (found in adipose tissue) and infertility (esp. in males, decrease testosterone, inhibit pituitary gland in driving gonadal function, interfere with sperm production) § DRUGS: o Autoprotection - Dronabinol, Nabilone, Sativex: § Dronabinol, Nabilone - Anti-emetics in cancer; stimulate appetite. § Sativex - analgesic; treat MS pain. o Autoimpairment - Rimonabant. § Rimonabant - Anti-obesity drug (off-market). · Blocks the feeling of hunger. depression and suicide associated, hence off market now.

Rimonabant

There is upregulation of CBRs in: o MS/pain/stroke patients - to regulate pain (protective effect) o Fertility/obesity - this is pathologic and may contribute to obesity (found in adipose tissue) and infertility (esp. in males, decrease testosterone, inhibit pituitary gland in driving gonadal function, interfere with sperm production) § DRUGS: o Autoprotection - Dronabinol, Nabilone, Sativex: § Dronabinol, Nabilone - Anti-emetics in cancer; stimulate appetite. § Sativex - analgesic; treat MS pain. o Autoimpairment - Rimonabant. § Rimonabant - Anti-obesity drug (off-market). · Blocks the feeling of hunger. depression and suicide associated, hence off market now.

Sativex

There is upregulation of CBRs in: o MS/pain/stroke patients - to regulate pain (protective effect) o Fertility/obesity - this is pathologic and may contribute to obesity (found in adipose tissue) and infertility (esp. in males, decrease testosterone, inhibit pituitary gland in driving gonadal function, interfere with sperm production) § DRUGS: o Autoprotection - Dronabinol, Nabilone, Sativex: § Dronabinol, Nabilone - Anti-emetics in cancer; stimulate appetite. § Sativex - analgesic; treat MS pain. o Autoimpairment - Rimonabant. § Rimonabant - Anti-obesity drug (off-market). · Blocks the feeling of hunger. depression and suicide associated, hence off market now.

Alteplase

Thrombolytic (tPA). recombinant tissue type plasminogen activator (rt-PA). § Thrombolytic drugs: o Alteplase - recombinant tissue-type plasminogen activator (rt-PA). § Oral. § A plasminogen analogue. § Converts plasminogen to plasmin which then degrades fibrin and dissolves the clot. § Indications for drug use - ARTERIAL THROMBI, VTE: o Stroke - first-line. o ST-elevated MI.

explain how a thrombus can form within a vein and identify the drugs used to treat deep vein thrombosis and pulmonary embolism

Thrombus more likely to form in a vein when risk factors affect the following: 1) Rate of blood flow, 2) Consistency of blood, 3) Blood vessel wall integrity (Virchow's triad). **DVT & PE treatment: Anticoagulants - dalteparin (SC, antithrombin activator), heparin (SC/IV, antithrombin activator), rivaroxaban (oral, fXa inhibitor), warfarin (oral, vitamin K antagonist)

Time related classification of adverse drug reactions

Time dependent vs time independent. **Drug interactions: 1) Pharmacodynamic: Related to the drug's effects in the body: Receptor site occupancy, or Interactions at different receptors, same organ/system. 2) Pharmacokinetic: Related to the body's effects on the drug: Absorption, distribution, metabolism, elimination. Metabolism probably most important. Cytochrome P450 system most crucial for handling of commonly used drugs.

Biological half-life

Time taken for the concentration of drug (in blood/plasma) to fall to half its original value

What must happen for a drug to achieve its effect?

To achieve its effect a drug must first be presented in a suitable formulation at an appropriate site of ADMINISTRATION and then (usually) ABSORBED and DISTRIBUTED through the body to its site of action. For the effect to wear off the drug must almost always be METABOLISED and/or EXCRETED with these residues being VOIDED (REMOVED) from the body. *So ADME*: (ADMINISTRATION) ABSORPTION DISTRIBUTION METABOLISM EXCRETION (REMOVAL)

Why might a patient be prescribed a muscarinic receptor agonist following abdominal surgery? To stimulate gastrointestinal activity/ To reduce gastric acid production/ To inhibit bladder emptying/ To increase gastrointestinal blood flow/ To increase wound healing.

To stimulate gastrointestinal activity

identify the drugs used in the prevention and treatment of atherosclerosis and the subsequent rupture of an atherosclerotic plaque

Treatment of atherosclerosis --> antiplatelet drugs*. o Antiplatelet drugs fall into 3 main categories: 1) COX inhibitors (aspirin) 2) P2Y12 receptor antagonists (clopidogrel) 3) GPIIb/IIIa receptor antagonists (abciximab) o Subsequent rupture of atherosclerotic plaque** --> thrombolytics. Thrombolytic drugs (alteplase) --> tissue plasminogen activator *Antiplatelets used for prophylaxis, not specifically treatment of atherosclerosis ** Thrombolytics can be used to treat ruptured plaques but mainly indicated for ischaemic stroke.

ACE inhibitors also inhibit the breakdown of bradykinin. True or False?

True

ACE inhibitors are used in the treatment of heart failure. True or False?

True

Anaphylaxis involves respiratory difficulty and/or hypotension. True or False?

True

Anaphylaxis is a type 1 hypersensitivity response. True or False?

True

Anaphylaxis requires previous exposure to the antigen. True or False?

True

Aspirin can induce bronchospasm. True or False?

True

Aspirin increases bleeding time. True or False?

True

Atypical neuroleptic drugs and second-generation antipsychotic drugs are the same thing. True/ False

True

Beta blockers are useful in angina because they decrease venous return. True/ False

True

Carbamazepine in an anticonvulsant drug. True/ False

True

Carbamazepine inhibits neuronal voltage-gated sodium channels. True/ False

True

Cocaine has local anaesthetic properties. True/ False

True

Concerning Parkinson's disease: COMT inhibitors can be used to increase the bioavailability of L-DOPA. True/ False

True

Concerning Parkinson's disease: L-DOPA is given in combination with a peripheral DOPA decarboxylase inhibitor to prevent its peripheral conversion to dopamine. True/ False

True

Concerning Parkinson's disease: Nausea, one of the acute side-effects of L-DOPA, can be treated using domperidone, a peripherally acting dopamine receptor antagonist. True/ False

True

Ethanol acts as a CNS depressant. True/ False

True

Ethanol can induce a pseudo-Cushing's syndrome. True/ False

True

The glycoprotein IIb/IIIa receptor is a target for anti-platelet drugs. True/ False

True

The typical neuroleptic drugs produce their beneficial clinical effects by antagonising dopamine D2 receptors. True/ False

True

Thiazides are used in the treatment of hypertension. True or False?

True

Thiazides are useful in the treatment of heart failure. True or false?

True

Thiazides often cause hyperglycaemia. True or false?

True

Thiazides promote K+ excretion. True or false?

True

Thrombolytics activates plasmin. True/ False

True

Warfarin effects can be reversed by Vitamin K. True/ False

True

When given repeatedly morphine may cause constipation. True or false?

True

Type 1 of drug antagonism: receptor blockade

Two types of antagonists: ® competitive ® irreversible ["Use-dependency" of ion channel blockers - more that the tissue is used, the more active it is, the more effective effect on the ion channel is e.g. Local anaesthetics]

Types of adrenoreceptors

Types of adrenoceptors -α1 - vasoconstriction, relaxation of gastrointestinal tract. -α2 - inhibition of transmitter release, contraction of vascular smooth muscle, CNS actions. -β1 - increased cardiac rate and force, relaxation of gastrointestinal tract, renin release. -β2 - brochodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis and gluconegenesis. -(β3 - lipolysis)

Classification of allergies

Types of allergic reactions: § Type 1 - immediate, anaphylactic. IgE. E.G. anaphylaxes with penicillin. § Type 2 - cytotoxic antibody. IgG, IgM. E.G. methyldopa and HA. § Type 3 - serum sickness (antibody-antigen complex). IgG, IgM. E.G. procainamide-induced lupus. § Type 4 - delayed-type hypersensitivity. T-Cell. E.G. contact dermatitis.

Risk factors for thrombosis

VIRCHOW'S TRIAD: 1.Rate of blood flow Blood flow slow/stagnating --> no replenishment of anticoagulant factors & balance adjusted in favour of coagulation. e.g. decreased when immobile. Slow = no replenishment of anti-coagulant factors. 2.Consistency of blood Imbalance between pro-coagulation & anticoagulation factors e.g. Factor 5 Leiden. 3.Blood vessel wall integrity Damaged endothelia --> blood exposed to pro-coagulation factors. e.g. during hypertension there's damage.

The action of ACh in the respiratory tract mimics the stimulation of which nerve?

Vagus (CN X)

Which one of the following pharmacodynamic properties is a competitive receptor antagonist most likely to display? High efficacy and zero affinity/ High potency and moderate affinity/ Zero efficacy and moderate affinity/ Zero potency and zero affinity/ Moderate efficacy and moderate affinity.

Zero efficacy and moderate affinity - An antagonist does not have efficacy (i.e have an effect), therefore it will have no potency (potency is a product of efficacy and affinity

Summarise the principle side effect profile of each class of anti-emetic drug

a) 5-HT3A receptor antagonists: headaches and constipation b) Histamine H1 receptor antagonists: drowsiness (quite beneficial though as want to go to sleep if feeling motion sickness) c) Muscarinic receptor antagonists: dry mouth and drowsiness d) Dopamine D2 receptor antagonists: galactorrhoea and extrapyramidal side-effects

PGE2 desirable actions

a) Bronchodilation (although there is evidence that PGE2 can desensitise β2adrenoceptors) b) Gastroprotection c) Renal salt and water homeostasis d) Vasoregulation (dilation and constriction depending on receptor activated) *hence maybe giving NSAIDS, may not be fully desirable

explain the processes of coagulation, platelet activation and the actions of fibrin

a) Initial - tissue Factor presentation --> Prothrombinase-mediated formation of factor IIa (thrombin) b) Amplification - thrombin (fIIa)-mediated platelet activation --> ADP activates P2Y12 receptor à COX & GPIIb/IIa c) Propagation - thrombin-mediated conversion of fibrinogen --> fibrin strands

Deliberate drug interactions

a) Levodopa + carbidopa: can use lower doses of levodopa as carbidopa reduced peripheral metabolism. b) ACEi + thiazides: treat HF. c) Penicillin's + gentamycin: treat severe staph. Infections. d) Salbutamol + ipratropium: beta-agonists and anti-muscarinics used in inhalers to treat asthma.

Mr Jones is a 62 year old man who is registering with a new GP. He feels well and has had no major medical problems. On routine examination his blood pressure is 170/105 mmHg. He is asked to rest for 5 minutes and his blood pressure is measured again: it is very similar and remains at this level on a couple of further visits over the next month. A) How would you describe Mr Jones' blood pressure? B) Mr Jones, who is overweight at 82kg and a height of 1.72m, is advised to lose weight, increase his exercise levels, reduce his salt intake and stop smoking. How might this help? C) On returning to see his GP Mr Jones has managed to reduce his weight to 74kg but his blood pressure has not changed. Consequently the GP prescribes Mr Jones 2.5mg bendrofluazide daily What are the two determinants of blood pressure? D) What sort of drug is bendrofluazide and how does it act to lower blood pressure? E) On returning to the GP eight weeks later Mr Jones blood pressure is measured at 165/100 mmHg. The GP tells Mr Jones to keep taking the bendrafluazide and further prescribes ramipril 2.5 mg daily. What class of drug is ramipril and why is this the best choice for a second line treatment in this case?

a) Mr Jones' blood pressure is significantly elevated. Treatment for hypertension is usually recommended if blood pressure is 140/90 mmHg or above on three separate occasions.In a majority of hypertensive patients there is no identifiable cause (it is idiopathic) and this is termed 'essential hypertension' b) i) Obesity is linked with increased risk (3-4 times) of hypertension and ischaemic heart disease among other things. While Mr Jones' BMI is 27.7 making him overweight rather than obese the extra weight will still increase his likelihood of hypertension, though the mechanisms are not well understood. Adipose tissue does contain components of RAS system, and the system is activated in obese individuals despite marked volume expansion. ii) Exercise will help encourage weight loss and has other cardiovascular benefits. Body weight can be thought of in terms of energy balance. A reduction in energy intake and/or an increase in energy expenditure will result in weight loss. Exercise increases circulation to the skin/muscles and widens the arteries. Improves renal function. iii) High salt intake in the diet results in expanded circulating volume and increased blood volume. This increased blood volume can put pressure on the heart by increasing cardiac filling pressure (pre-load). A reduction in salt intake will have a small but significant effect in most people. Some controversy. Approx 30% HT patients are sensitive to salt and found to have low levels of rennin. Salt restriction should help in these patients. Salt metabolism is complex. iv) Smoking has been associated with a 60% increase in the mortality in men aged 55-64 from coronary heart disease. Nicotine has been shown to have vasoconstrictor effects, both direct and indirect via the sympathetic nervous system. c) Blood pressure = Cardiac output x Peripheral vascular resistance. d) Bendrofluazide belongs to group of diuretics called thiazides, which act on the distal tubule of the kidney to reduce the active reabsorption of sodium and chloride ions. The drug acts by inhibiting the Na+ / Cl- co-transport system. The initial fall in blood pressure is thought to be due to the decreased blood volume resulting from indreased diuresis. Later phase however seems to be due to a direct effect on the blood vessels themselves although the mechanism by which this occurs is obscure. Subtle alterations in the contractile response of vascular smooth muscle. e) Ramipril is an angiotensin converting enzyme inhibitor (ACE Inhibitor). *Effects of Angiotensin II in the body: a) Vasoconstriction (particularly in the kidney) b) Increased release of NA from sympathetic nerve terminals - reinforcing vasoconstriction c) Stimulation of proximal tubular reabsorption of Na+ - increasing blood volume. d) Secretion of aldosterone from adrenal cortex - further increasing Na+ reabsorption and increased blood volume. The thiazide diuretic bendrofluazide increases the concentration of Na+ retained in the distal tubule of the kidney (decreasing the Na+ concentration in the filtrate) thereby activating the renin-angiotensin system by stimulating renin release from the juxtaglomerular cells. This actually increases the response to an ACE inhibitor, which then suppresses the renin-angiotensin system. Afro-Caribbeans and elderly individuals, who tend to have low renin hypertension, respond less well to monotherapy with ACE inhibitors. Inhibition of ACE (kininase II) also leads to accumulation of kinins including bradykinin which promotes vasodilator activity and may contribute to the overall effectiveness of ACE inhibitors.

Mrs Smith is a 71 year old woman, who has long-standing atrial fibrillation. Recently widowed she has moved in with her daughter and family, with all the upheaval in her life however she has not been taking her prescribed medication. On registering with her daughters GP Mrs Smith is discovered to have a ventricular rate of 120 /min and complains of becoming very short of breath on exertion and has swollen ankles. a) The GP prescribes Digoxin and warfarin. Why would the GP prescribe these particular drugs? b) What are there mechanisms of action?

a) Mrs Smith has a very high ventricular rate (normal rate usually below 80 beats/min at rest) and is showing signs of cardiac failure. i) Digoxin is a cardiac glycoside, which is commonly used to treat cardiac failure in association with rapid atrial fibrillation. Atrial fibrillation has been shown to predispose patients to atrial thrombus formation and subsequent systemic emboli, which commonly cause stroke. ii) Consequently Warfarin, an oral anticoagulant, is given prophylactically to prevent thromboembolism. b) Digoxin slows conduction at the atrioventricular node, partly by a direct effect and partly via activation of the vagus nerve. In any case the cellular mechanism is the same - inhibition of the Na+/K+ ATPase. This also induces some increase in contractile force in the heart (positive inotropic effect), though the importance of this is controversial - increase in intracellular calcium. Digoxin blocks Na+/K+ ATPase (competes with potassium for active site), so sodium builds up in the cell. This causes increased intracell calcium levels due to Na+/Ca2+ exchanger. i) Digoxin currently sidelined due to increased risk of death in patients with atrial fibrillation. Could be due to increase in platelet activity. Currently replaced with beta blockers. ii) Warfarin blocks the formation of Vitamin K by inhibiting the hepatic reductase enzyme that converts vitamin K to its active (hydroquinone) form. Vitamin K is essential for the formation of the clotting factors II, VII, IX and X. Consequently warfarin affects blood clotting time.

Role of PGE2 in gastric cytoprotection (COX-1)

a) PGE2 downregulates HCl secretion (dose-dependant reduction) b) PGE2 stimulates mucus and bicarbonate secretion **hence NSAIDS can increase the risk of ulceration. About half the deaths from NSAIDs result from gastrointestinal causes. **solution? maybe selectively inhibit COX2 can spare it. o COX-1 and COX-2 with different (but overlapping) cellular distributions •Aspirin is COX-1 selective and particularly bad at causes ulcers •Maybe COX-2 selective NSAIDS won't cause ulcers •Coxib family: selectively reversibly inhibit COX-2 (example: celecoxib)

In which parts of the autonomic nervous system is the neurotransmitter Acetyl Choline (ACh) found?

a) Released from all preganglionic nerve terminals , both sympathetic and parasympathetic. b) Released from all parasympathetic postganglionic nerve terminals. c) Released from postganglionic sympathetic nerve terminals in sweat glands. d) Released from sympathetic fibres innervating adrenal medulla (as if the adrenal medulla were a ganglion). e) (Also released at NMJ, although this is not part of the ANS and hence not required for this question).

What is first pass metabolism? Apart from the liver list two places it can occur? Describe enterohepatic cycling?

a) What is first pass metabolism? Concentration of a drug is greatly reduced before it enters the systemic circulation. b) Apart from the liver list two places it can occur: Stomach, small intestine. c) Describe enterohepatic cycling: When a drug is administered it is mostly absorbed into the bloodstream from the small intestine --> enters portal circulation to the liver à drug is secreted into the bile of the liver à gall bladder secretes bile containing drug back into the intestine and the process starts again.

Which of the following drugs would you administer to treat an atropine overdose? A.Bethanechol B.Ecothiopate C.Hyoscine D.Physostigmine E.Pralidoxime

a) bethanechol - Ach cholinomimetic, would outcompete atropine (muscarinic receptor agonist); b) ecothiopate - Ach cholinomimetic (Irreversible anticholinesterase.); d) physostigmine - is reversible - anti-cholinesterase * NOT hyoscine as it is also an antagonist; pralidoxime - recovers Ach esterase

What other metabolites of paracetamol would you expect to be formed from phase 2 reactions and name the enzymes/co-substrates necessary, given the list of common phase 2 reactions listed below: Methylation Acetylation Sulphation Glucuronidation Amino acid conjugation Glutathione conjugation

a) methylation : enzyme is methyltransferase; co-substrate: S-adenonysl methionine (SAM) b) acetylation : enzyme = acetyltransferase; co-substrate= acetyl coA sulphation: enzyme = sulphyl transferase; co-substrate = PAPS (3-phosphoadenoise- 5'phosphosulphate) glucuronidation: enzyme = UDP glucoronysl transferase; co-substrate = UDP glucuronic acid. amino acid conjugation: aminotransferase; co-subsrtate: glutamate, glutamine, glycine (makes more polar) glutathione conjugation: enzyme = glutathione s transferase; co-substrate = glutathione (LAZ's notes has)

Mr E is a 62 year old man who was diagnosed as HIV-positive last year. His current symptoms include dry mouth, light sensitivity, problems emptying his bladder and excessive sweating - symptoms associated with his ANS. a) Which of these symptoms could be caused by either inhibiting the SNS or treating the patient with a muscarinic receptor antagonist? b) how were the different branches of the ANS affected by the HIV? c) How would you interpret the following set of results: BP -130/80mmHdg; total cholesterol - 6.4mmol/l; HIV + viral load - 20 copies/ml? d) Mr E was treated with a beta blocker in addition to the standard triple therapy for hypertension. Why might the beta blocker cause cold extremities? e) Older individuals can often demonstrate a decreased response to beta blockers. Why might this be the case?

a) reduced sweating b) decreased PNS and SNS c) normal BP, high cholesterol, low viral load d) prevents peripheral vasodilation e) elderly may have a reduced number of beta-adrenergic receptors f) look at pic: beta blocker induced reflex vasoconstriction is increased due to reduced baroreceptor sensitivity.

Examples of local vs systemic effect of drugs: a) salbutamol - inhale b) aspirin - oral c) betnovate (betamethasone) - dermal steroid cream d) cannabis - inhale e) antacid - oral f) nicotine - dermal

a) salbutamol - local to lungs b) aspirin - systemic c) betnovate (betamethasone) - local to skin area d) cannabis - systemic e) antacid - local to stomach f) nicotine - systemic

How can drugs cross lipid barriers?

a) simple diffusion b) diffusion across aqueous pores c) carrier mediated transported d) pinocytosis - diffusion across aqueous pores is least relevant as need to be VERY small to come across - water soluble molecules need help to cross the lipid membranes

Anti-convulsants: recognise that anti-convulsant therapy is determined by the seizure type coupled with pharmacodynamics/pharmacokinetic properties of specific anti-convulsant drugs

a)Inhibition of VGSCs (e.g. Carbamazepine, lamotrigine) - Tonic-clonic, partial b)Inhibition of VGCCs (e.g. Ethosuximide) - Absence c)Inhibit vesicular release (e.g. Levetiracetam) - Myoclonic d)Inhibit glutamate receptors (e.g. Topiramate) - Myoclonic e)Enhance GABA channel activity (e.g. Diazepam) - status epilepticus f)Inhibit GABA metabolism (e.g. Valproate) - all types

Seizures: recognise the different seizure types

a)Tonic-clonic seizures: loss of consciousness --> muscle stiffening --> jerking/twitching --> deep sleep --> wakes up b)Absence seizures: brief staring episodes with behavioural arrest c)Tonic/atonic seizures: sudden muscle stiffening/sudden loss of muscle control d)Myoclonic seizures: sudden, brief muscle contractions e)Status epilepticus: > 5 min of continuous seizure activity f)Simple partial: retained awareness/consciousness g)Complex partial: impaired awareness/consciousness

a-Blockers use for HT

a-Blockers: E.G. Prazosin, Phentolamine. § a-blockers block a1-mediated vasoconstriction. § Prazosin is an a1-antagonist. § Phentolamine is an a1/a2 antagonist. o Action against a2 blocks the -ve feedback of NA release and so there is an enhanced NA release and SNS response. o This can lead to increased HR (not reflex).

Certain b-blockers may produce adverse effects in some people. What are these likely to be?

a. Airways - (you have 2 lungs therefore b2!) non-selective beta-blockers can cause bronchoconstriction so bad for people with asthma and COPD. b. Liver - (b2) gluconeogenesis and glycogenolysis will be blocked by a beta blocker as the adrenaline usually will increase glucose in the blood so bad for people with diabetes.

Why would a doctor prescribe buprenorphine to ween someone off methadone?

a. As buprenorphine is a partial agonist and so it wouldn't be possible to OD from it and the patient also cannot achieve the same full high from it. b. Pushes the dose response curve down and to the right.

Can you explain why a sympathomimetic drug (dipivefrine) and a beta-blocker (timolol) can both be used to treat glaucoma?

a. Dipivefrine will cause radial muscles to constrict. b. SNS activity on A1 receptors in blood vessels in the eye will cause vasoconstriction and reduce blood flow into the eyes and reduce aqueous humour production (and reduce IOP). c. Decreased blood flow will also increase IOP by reducing recycling

Can you identify the drug target site of heroin in the body and describe how heroin would access the drug target site? Describe the 4 main categories of drug target sites.

a. Heroin is an agonist drug that is IV injected and then travels to the brain via the systemic circulation and then binds to the opioid receptor in the brain (as heroin is a lipophilic drug, it can pass the BBB). b. receptors (heroin), ion channels (LAs), enzymes (COX with aspirin), transport systems (antidepressants) i. Receptor is distinct because it only has ONE function - to be a receptor. The other 3 forms of drug target site

Give a short account of the pharmacology of b-blockers, explaining why they are effective in the treatment of hypertension, tachycardia and arrhythmia

a. Hypertension - b-blockers antagonise the actions of adrenaline and noradrenaline in the heart on the b1 adrenoceptor which then reduces the chronotropic and ionotropic effects of the heart. The b-blockers also antagonise the actions of adrenaline and noradrenaline on the renin-angiotensin system when binding to b1 receptors in the kidneys to reduce renin secretion and thus AngII synthesis. b. Tachycardia - b-blockers antagonise the actions of adrenaline and noradrenaline in the heart on the b1 adrenoceptor which then reduces the chronotropic effects of the heart ONLY. c. Arrhythmia - b-blockers antagonise the actions of adrenaline and noradrenaline in the heart on the b1 adrenoceptors in the AV-node and so reduce the ability of the atria to transmit irregular signals

Mr E is a 62 year old man who was diagnosed as HIV-positive last year. His current symptoms include dry mouth, light sensitivity, problems emptying his bladder and excessive sweating. He is on standard HIV medication and six months ago ritonavir was also added. He has hypertension and has been taking standard triple therapy for six months. Assign the following effects to either stimulation/inhibition of the parasympathetic or sympathetic nervous system and for each effect identify the precise location where tissue function is influenced.

a. Light sensitivity: i. Parasympathetic inhibition to the sphincter pupillae (circular muscles) by muscarinic receptor action in CN II. b. Problems with bladder emptying: i. Parasympathetic inhibition to bladder sphincters and detrusor muscles via muscarinic receptor action. c. Reduced sweating: i. Decreased sympathetic tone to sweat glands via muscarinic receptors. d. Dry mouth: i. Parasympathetic inhibition to parotid, sublingual and submandibular glands to muscarinic receptors via CN VII. HIV can cause autonomic peripheral neuropathy which destroys muscarinic receptor nerve endings. If both arms of the ANS are being damaged, at rest with the PNS dominant, the effects of the PNS will be more inhibited and thus more pronounced.

What do you think are some of the problems associated with drugs applied topically to the eye, in terms of local and systemic bioavailability? Consider the answer to the first part of this question and then identify the adverse effects that may be associated with the use of Dipivefrine and Timolol eye drops. Think about the selectivity of these two drugs and consider how you might reduce these adverse effects.

a. Removed through tear ducts, not absorbed effectively. b. When the drug is inside the eye, it has access to the entire systematic system. c. Timolol is a non-selective beta-blocker and so if it gets into the systematic circulation, it can affect the heart.

Explain the difference between a "single blind, non-crossover trial" and a "double-blind crossover trial". List the advantages and disadvantages.

a. Single blind, non-crossover - subject doesn't know the drug. One group is given the drug, the other the placebo and NO crossover. Adv. No bias in subjects, lower cost. Dis. Adv. Bias in prescriber. b. Double blind, crossover - subject and clinician don't know drug. Each group gets both the drugs in different weeks. Adv. No bias, tight data set with reduced variables. Dis. Adv. Dropout rate, cost.

Vasoconstricting agents

a. Sumatriptan and Ergot alkaloids: Sumatriptan is an agonist at 5HT1D receptors and causes vasoconstriction of some large arteries and inhibits trigeminal nerve transmission. It is used to treat migraine attacks, but is contraindicated in patients with coronary disease as it also causes coronary vasoconstriction. Other ergot alkaloids are also used in migraine and probably act as 5HT1 receptor partial agonists but their usefulness is limited by side effects. b. Sympathomimetic agents: Adrenaline, the endogenous catecholamine, produced by the adrenal gland is used in cardiac arrest and anaphylactic shock.

A toxic dose of heroin produces a similar effect on the eye to the organophosphates. What is the effect and how does the mechanism of this effect differ between the two drugs? With regards to heroin, this effect combined with signs of respiratory depression is almost diagnostic - why do you think this is so? What happens to the eyes if toxicity continues and asphyxia occurs?

a. There are opioid receptors in the oculomotor nerve therefore heroin will cause pupil constriction through disinhibition of the oculomotor nerve (blocks the GABA inhibitory neurones) however if toxicity continues, asphyxia causes nerve damage which causes fixed dilation of the pupils. b. The organophosphates are anticholinesterases and so block the breakdown of ACh which causes a depolarising block after a massive stimulation (constriction and then dilation).

What were the effects of Tropicamide and pilocarpine on the ocular parameters? How can one explain these effects? Why was pilocarpine used as an anti-glaucoma medication and can you think of a practical reason why it has been superseded by other agents? How may the effects of tropicamide be used in the clinical setting?

a. Tropicamide - enlarged pupil, no response to light, accommodation distance increases. b. Pilocarpine - smaller pupil, no response to light, closer accommodation distance. c. Pilocarpine stimulates the ciliary muscles which in turn causes the trabecular meshwork to open up, thus improving the rate of aqueous humour recycling thus releasing pressure in the eye. d. Pilocarpine is short lasting and so isn't the best anti-glaucoma medication. e. Tropicamide is used to examine the retina

The mechanism of action of Azathioprine in IBD: a.Interferes with purine biosynthesis b.Is a direct reduction of protein synthesis in the GI tract c.Is blocked by co-administration with allopurinol d.Means that it increases side-effects caused by infliximab e.Needs activation of the drug by metabolism to 5-ASA

a.Interferes with purine biosynthesis

Labetalol

a1+b1 dual-action antagonist (higher ratio of b1 to a1, 4:1): o Lowers BP via reduction in TPR. o Induces a reduction in HR or CO but this effect wanes with chronic use. *(like carvedilol - alpha and beta antagonist)

What is airway resistance and what factors contribute to airway resistance in man?

airway resistance - how easily air moves in and out. o Resistance is the amount of pressure required to deliver a given flow of gas and is expressed in terms of a change in pressure divided by flow. The standard units of resistance are cm H20/L/second and the normal value for an adult is very low (~ 0.5 - 1.5 cm H20/L/sec) and arises from recoil and pressure in the normal anatomy (airway diameter and length). o In contrast, in disease this value may be 100.0 cm H20/L/sec or higher. Anything which reduces the airway lumen will increase the resistance, so in disease states this could be mucus plugs, bronchoconstriction, a reduction in lung volumes or lung fibrosis (because the lungs collapse down/ lose elasticity and put pressure on the airways, squashing those which lack cartilage to keep them open) or inhaled foreign bodies. o There are other factors (laminar vs turbulent air flow, density of inspired gas etc but these are relatively minor under most circumstances). Intubating a patient will increase their airway length so will also increase resistance. The later stages of pregnancy also increase resistance as the growing foetus pushes abdominal contents upwards and compresses the thorax. **most resistance in bronchioles. in emphysema, alveoli break down and hence less tension on bronchioles and they collapse. **in pregnancy, as baby grows upwards into thoracic space, woman can't flatten out diaphragm fully and can't expand lungs fully.

Phenylephrine what is it? Why might it be used as a decongestant?

alpha 1 agonist. a1>>a2>>>b1/b2. ØChemically related to adrenaline - more Ø Resistant to COMT but not MAO - significance is COMT is more peripheral and MAO is more central. phenylephrine is more longer lasting as peripheral agent. *Why might it be used as a decongestant?* - Vasoconstriction - less white cell infiltration, less fluid exudation and less build up, brings up BP - Mydriatic - dilate pupil - Nasal decongestant

Botulinum toxin

an acetylcholine antagonist; prevents release by terminal buttons. blocks snare complex involved in Ach exocytosis. very strong and very little needed to shut down nerve function. BUT can be used in botox as it paralyses the muscle. Botulinum toxin is the most toxic protein known. A single gram of crystalline toxin, evenly dispersed and inhaled, would kill more than 1 million people. **Parasympatholytics: § One of the most toxic proteins know. § Botulinum binds to the ACh vesicles and stops them docking with the inner membrane. o Forms SNARE complexes.

Acetanilide is a pro-drug of paracetamol. Acetanilide causes methemoglobinemia and as a result was removed from the market and replaced with paracetamol. Explain the term pro-drug and show what reaction is involved in the transformation of acetanilide to paracetamol.

aromatic oxidation from acetanilide to paracetamol. pro-drug is inactive compound that becomes activated by body's metabolism. ratio of drugs depends on enzyme affinity: mass balance analogy

Basal control of heart rate - as BP drops what happens to baroreceptor rate?

at rest, the PNS is dominant (intrinsic rate is 100-110 bpm). When BP drops, baroreceptor firing rate drops, less inhibition of sympathetic NS, more stimulation of parasympathetic NS --> increases heart rate and causes vasoconstriction to restore normal BP

What are the three principal efferent outputs of CNS?

autonomic, somatic and neuroendocrine

If a log dose response curve for a full agonist with a fixed dose of a partial agonist for the same receptor were administered at the same time, how would the log dose response curve compare with the curve produced in the presence of the full agonist alone? a)A higher maximal response - additive effect. b)Dose response would be a parallel shift to the right c)Superimposed. d)The dose response curve would be similar but with a lower maximum e)There would be no response at all.

b)Dose response would be a parallel shift to the right. If have partial agonist with full agonist - getting competition for receptor. If does of full agonist is low enough, partial agonist will compete fairly well. The curve for full agonist will go down; but as keep increasing concentration of full agonist will completely outcompete partial agonist --> parallel shift to the right. Most competitive agonist have a degree of partial agonistic activity.

Salbutamol (ventolin)

b2 agonist. b2>>b1>>>a1/2. §Synthetic catecholamine derivative with relative resistance to MAO and COMT. * get muscle relaxation. leads to cAMP, muscle relaxation and potassium efflux. *Clinical Uses* 1) Treatment of Asthma - b2-relaxation of bronchial smooth muscle - inhibition of release of brochoconstrictor substances from mast cells. 2) Treatment of threatened premature labour - b2-relaxation of uterine smooth muscle ØSide effects- Reflex tachycardia, Tremor, blood sugar dysregulation

Why might β2 receptor stimulation be a problem?

b2-stimulation in vascular smooth muscle in skeletal muscle results in fall in venous blood pressure which triggers a reflex tachycardia via the stimulation of baroreceptors.

morphine rule

before used to say that for compound to have an effect, had to look like morphine: tertiary nitrogen, quarternary carbon, phenyl group.

Isoprenaline

beta agonist. ß1=ß2>>>>α1/2. ØChemically related to adrenaline - more resistant to MAO and uptake 1 - less easily broken down in brain. o Clinical uses - Cardiogenic shock - Acute heart failure - Myocardial infarction beta agonists used to increase cardiac output.

In the past, Isoprenaline (non-selective β-adrenoceptor agonist) has been used to treat asthma, however it was discontinued due to patients experiencing fatal reflex tachycardia. Why can the use of isoprenaline result in reflex tachycardia?

beta-2 adrenoreceptor stimulation causing arteriolar vasodilatation. Topic Summary: Reflex tachycardia is a condition that results in a sudden drop in blood pressure. As a result, arterial baroreceptors decrease firing causing a decrease in sympathetic suppression and parasympathetic stimulation to the heart.

Pharmacokinetic Drug Interactions

body's effects on the drug - e.g. absorption, distribution, metabolism, excretion. a) Alteration in absorption - CHELATION: o Irreversible binding in the GI-tract, for example, antibiotics to metal ions or calcium to form chelates that prevent absorption of the antibiotic. o Tetracyclines, quinolone antibiotics - ferrous sulfate (Fe+2), antacids (Al+3, Ca+2, Mg+2), dairy products (Ca+2) b) Protein-binding interactions - not usually clinically significant but some are (e.g. warfarin). o Warfarin is 99% albumin-bound so anything to decrease that will increase the free warfarin so there is more anti-coagulative effects. o Competition between drugs for protein or tissue binding sites: -Increase in free (unbound) concentration may lead to enhanced pharmacological effect. o Many interactions previously thought to be PB interactions were found to be primarily metabolism interactions. o PB interactions are not usually clinically significant but a few are (mostly with warfarin). c) Drug metabolism AND excretion: o Drugs can either be (1) directly excreted, (2) undergo Ph1 metabolism and be excreted, (3) undergo Ph1 and Ph2 and then be excreted or (4) only undergo Ph2 and then be excreted. § Phase 1 metabolism = oxidation (main one), reduction, hydrolysis. § Phase 2 metabolism = conjugation (glutathione, amino-acid), glucuronidation, sulphation, acetylation and methylation.

Hardy-Weinberg law

both allele and genotype frequencies in a population remain constant- that is, they are in equilibrium - from generation to generation unless specific disturbing influences are introduced.

Clinical uses of Hexamethonium and Trimetaphan?

but their side effects are too risky; too many potential risks to use therapeutically 1) Hexamethonium - the first anti-hypertensive drug used but LOTS of side effects as very general. o Primarily an ion-channel blocker (so not a lot of affinity). 2) Trimetaphan - used for when you want hypotension during surgery, IV-administered, short acting. o Primarily a receptor antagonist (so has affinity). o BOTH drugs can however both antagonise and block nicotinic receptors. § a-bungarotoxin is an example of a GBD that is irreversible (used by snakes). o This drug binds mainly to somatic nicotinic receptors (NRs) whereas the GBDs above bind to autonomic NRs.

The figure below shows a GABAergic nerve terminal. Each of the four classes of drug target are represented on this figure. You administer a drug that you know acts as an inhibitor/blocker for the respective target. After administration of the drug, the amount of GABA in the synapse increased. Which of the numbered targets did the drug act on? a) 1 b) 2 c) 3 d) 4 e) 5

c) 3

Thirty minutes after administration, blood levels of a drug are higher in the hepatic portal venous system than in the major arteries (systemic blood levels). Which route of administration was utilised for this drug? a)Inhalational b)Intravenous c)Oral d)Sublingual e)Transdermal

c)Oral - for all the others would expect to see higher in systemic blood before hepatic.

A 65-year-old lady is diagnosed with closed-angle glaucoma and started on a course of pilocarpine eye drops. What is the mechanism of action of a cholinomimetic used for glaucoma treatment?

causes contraction of sphincter pupillae, increasing drainage of aqueous humour via the canals of schlemm. **Topic Summary: Parasympathetic innervation of the eye results in contraction of the ciliary muscle causing the lens to bulge required in accommodation for near vision, contraction of the sphincter pupillae to constrict the pupil, and lacrimation.

Methyldopa side effects

causes so much hypotension can be limiting. does dry mouth as well

Where does arachidonic acid come from?

cell membrane phospholipids. § NSAIDs work by inhibiting the production of a family of lipid mediators called "prostanoids". The term "prostanoid" covers two sub-groups: the prostaglandins and the thromboxanes. § NSAIDS work by inhibiting the enzyme cyclo-oxygenase (COX) which is the rate limiting step for the production of all prostanoids from their parent compound, arachidonic acid. § Prostanoids are ubiquitous compounds, found in most tissues. § They cannot be stored, but are released immediately they have been synthesised. § They act through a large number of different, specific prostanoid receptors to produce a highly complex array of actions, some, but not all of which, are pro-inflammatory. § The diversity of actions of prostanoids explains why inhibiting their synthesis with NSAIDs can have many unwanted effects.

A 40-year-old patient with a history of diabetes and hypertension presents with closed-angle glaucoma. Which class of drugs would be most suitable to treat his glaucoma?

cholinomimetic. Topic Summary: When given a question like this, think about which classes of drugs can be used to treat glaucoma, their mechanisms of action and their contraindications. Although there may be more than one class that can be used, think about what else the drug will effect and relate it to the patient's history.

The following graph shows the variation in pH across the GI tract. Amoxicillin is a weak base with a pKa of 7.4. In which region of the GI tract would amoxicillin be best absorbed?

distal small intestine: as it is the part of GIT that has highest pH. here the pH is 7.5 , whereas amoxicillin has a pKa lower than this so will be mostly unionised and hence better absorbed. Topic summary: The pKa tells us the pH at which 50% of the drug is found in its unionised form. Drug absorption is affected by 3 factors: The lipid solubility of the unionised drug, the pKa of the drug and the pH of the surrounding medium. In reality the amount of drug that crosses a membrane is defined by the state of ionisation and for absorption to be most efficient, the drug should be mostly unionised.

Rearranging henderson-hasselbalch to work out ratio of ionised to unionised form of molecule

do anti log of pKa - pH, and gives the ratio of (AH/A-) or (BH+/B)

what do antagonists not contain?

don't contain efficacy. only agonists contain efficacy. both possess affinity.

Why did Nicholas' friend inject ten times more heroin i.v. in order to achieve the same level of response? What mechanisms could account for this phenomenon?

drug tolerance. Could be due to: down-regulation of receptors, change in receptors (desensitisation), physiological adaptation -What additional mechanisms can cause a tolerance to alcohol? increased metabolism in liver, exhaustion of mediator stores ( pharmacokinetic factors )

Mr E on antihypertensives, statins and HIV medication. Several months later, he develops a chest infection and GP prescribes clarithryomycin and tells Mr E to stop taking statin due to dangerous drug interaction. not long after starting the clarithryomycin Mr E shows confusion signs. Consider table and suggest why Mr E is confused now

dual drug interaction - both inhibit CYP3AD enzyme. both ritonavir and clarithryomycin are metabolised by same enzyme.

The following diagram shows how the plasma concentration of drug X changes over time. What is represented by the range indicated by A? clearance/duration of action/lag period/ bioavailability/ biological half-life

duration of action: shows the total time the drug is above MEC and thus exerting its therapeutic effect. o not clearance - volume of plasma that is completely cleared of a drug per unit time. hence it is expressed as a rate and not a simple range of time. o not lag period - time taken for adrug to be absorbed in sufficient quantity to exert its pharmacological effect. i.e. time taken after 0 minutes for it to reach the minimum effective conc. o not bioavailability - is prop of administered drug that is available within the body to exert its pharmacological effect. is assessed by area under the plasma level-time curve. o not biological half-life - is time taken for the plasma conc of a drug to fall to half its original value Topic Summary: In the diagram, we can see labelled the minimum effective concentration (MEC), and A is the total time that the drug is above the MEC. Below the MEC the drug is not able to exert its effect.

Why has the number of deaths from paracetamol overdose fallen steadily in England and Wales? a)More livers are available to provide transplants for patients after paracetamol overdose b)Paracetamol can only be purchased in a formulation which contains the antidote c)Paracetamol has been replaced by better analgesics d)Paracetamol is now only available on prescription e)The quantity of paracetamol which can be purchased over the counter is restricted by law

e) The quantity of paracetamol which can be purchased over the counter is restricted by law

Inhibition of which enzyme will reduce platelet aggregation with fewest side effects? a)COX-1 b)COX-2 c)Prostacyclin synthase d)Prostaglandin E synthase e)Thromboxane A2 synthase

e) Thromboxane A2 synthase Yes- Thromboxanes causes platelet aggregation, but not much else

Assertion: Inhibition of PGI2 synthesis by low dose aspirin decreases the risk of stroke Because : Decreased PGI2 reduces platelet aggregation a)Assertion true, reason true and explains assertion b)Assertion true, reason true but does not explain assertion c)Assertion true, reason false d)Assertion false, reason true e)Assertion false, reason false

e)Assertion false, reason false o Explanation: Synthesis of PGI2 (prostacyclin) is inhibited by low dose aspirin, but it is not this action which decreases the risk of stroke, because PGI2 actually reduces platelet aggregation. It's the inhibition of thromboxane synthesis

Diuretics - Potassium sparing diuretics

e.g. AMILORIDE/ SPIRONOLACTONE o acts right at end of tubule so don't lose sodium when trying to reabsorb sodium through Na/K ATPase. o aldosterone would increase sodium reabsorption through Na+ channels and Na/KATPase. Diuretics block effect of aldosterone. § Spironolactone - aldosterone receptor agonist. § Amiloride - aldosterone-sensitive Na+ channel inhibitor (Blocks). § These are not very powerful diuretics - 5% as ending right at the end. o Inhibit sodium reabsorption in the early DCT. § Also cause decreased reabsorption of Na+ in the DCT and increased H+ retention. o Due to effects of decreased Na+/H+ exchange. a) Action on Na+ reabsorption: Inhibit Na+ reabsorption (and concomitant K+ secretion) in early distil tubule - 5% b) Action on H20 reabsorption: tubular fluid osmolarity = ¯ H2O reabsorption in the collecting duct. c) Other effects: ¯ reabsorption of Na+ to distal tubule H+ retention (¯ Na+/H+ exchange)

TCAs - MOA

e.g. Amitriptyline o three ring structure; either dibenzazepines or dibenzcycloheptenes. § Mechanism of action: o Monoamine re-uptake inhibitor: NA=5-HT >> DA - hence increase NA and 5-HT levels. o Also acts on: § a2 - block pre-synaptic inhibition of NA release. § mAChR. § H2 (histamine) receptors. § 5-HT receptors. o There is delayed down-regulation of β-adrenoceptors & 5-HT2 receptors by TCAs. The time-course of this down-regulation correlates well with the clinical onset of symptom relief. *** Pharmacokinetics: o Oral administration. o Highly PPB - 90-95%. o Hepatic metabolism - to ACTIVE metabolites --> excreted in the urine (glucuronide conjugates). o Plasma T1/2 = 10-20 hours - dose once daily **§Unwanted effects: 1) Therapeutic doses: § Atropine-like effects - anti-PNS effects such as dry mouth, constipation, etc. § Postural hypotension - due to effects on vasomotor centre (possibly involving a2 receptors) § Sedation - due to effects on H1 antagonism (can be a good thing if having decreased sleep at night) 2) Acute toxicity: § CNS - excitement, delirium, seizures --> coma, respiratory depression. § CVS - cardiac dysrhythmias --> VF & sudden death. §Care - Often used for attempted suicide!

Pharmacokinetics of TCAs

e.g. Amitriptyline o three ring structure; either dibenzazepines or dibenzcycloheptenes. § Mechanism of action: o Monoamine re-uptake inhibitor: NA=5-HT >> DA - hence increase NA and 5-HT levels. o Also acts on: § a2 - block pre-synaptic inhibition of NA release. § mAChR. § H2 (histamine) receptors. § 5-HT receptors. o There is delayed down-regulation of β-adrenoceptors & 5-HT2 receptors by TCAs. The time-course of this down-regulation correlates well with the clinical onset of symptom relief. *** Pharmacokinetics: o Oral administration. o Highly PPB - 90-95%. o Hepatic metabolism - to ACTIVE metabolites --> excreted in the urine (glucuronide conjugates). o Plasma T1/2 = 10-20 hours - dose once daily §Unwanted effects: 1) Therapeutic doses: § Atropine-like effects - anti-PNS effects such as dry mouth, constipation, etc. § Postural hypotension - due to effects on vasomotor centre (possibly involving a2 receptors) § Sedation - due to effects on H1 antagonism (can be a good thing if having decreased sleep at night) 2) Acute toxicity: § CNS - excitement, delirium, seizures --> coma, respiratory depression. § CVS - cardiac dysrhythmias --> VF & sudden death. §Care - Often used for attempted suicide!

Unwanted effects of TCAs

e.g. Amitriptyline o three ring structure; either dibenzazepines or dibenzcycloheptenes. § Mechanism of action: o Monoamine re-uptake inhibitor: NA=5-HT >> DA - hence increase NA and 5-HT levels. o Also acts on: § a2 - block pre-synaptic inhibition of NA release. § mAChR. § H2 (histamine) receptors. § 5-HT receptors. o There is delayed down-regulation of β-adrenoceptors & 5-HT2 receptors by TCAs. The time-course of this down-regulation correlates well with the clinical onset of symptom relief. §Unwanted effects: 1) Therapeutic doses: § Atropine-like effects - anti-PNS effects such as dry mouth, constipation, etc. § Postural hypotension - due to effects on vasomotor centre (possibly involving a2 receptors) § Sedation - due to effects on H1 antagonism (can be a good thing if having decreased sleep at night) 2) Acute toxicity: § CNS - excitement, delirium, seizures --> coma, respiratory depression. § CVS - cardiac dysrhythmias --> VF & sudden death. §Care - Often used for attempted suicide! § Drug interactions: o PPB - as very PPB, there can be a massive increase of bioavailability if co-administered with something that displaces it from the plasma proteins - e.g. aspirin, phenytoin. o Hepatic enzymes - drugs that compete with the metabolising hepatic enzymes. o Potentiation - drugs that potentiate the effects of the CNS depression - e.g. alcohol. o Antihypertensives

SSRIs MOA and pharmacokinetics

e.g. Fluoxetine § Mechanism of action: o 5-HT re-uptake inhibitor. o Has less bad side effects so safer in ODs unlike TCAs. not prone to cheese reaction like MAOIs. o But, less effective against severe depression. § Pharmacokinetics: o Oral administration. o Plasma T1/2 = 18-24 hours. o Delayed onset of action - 2-4 weeks. o Fluoxetine competes with TCAs for hepatic enzymes so avoid co-administration --> toxic effects?

MAOIs MOA

e.g. Phenelzine § Mechanism of action: o MAO enzymes: § MAO-A breaks down NA & 5-HT - key MoA! § MAO-B: breaks down DA - e.g. Selegiline. o Most are non-selective MAOIs. o Irreversible inhibition leads to a long duration of action. o Effects: § Rapid effects - increase cytoplasmic (not enhanced release but more leakage) NA, 5-HT. This is due to less breakdown of monoamines as the drugs get into the terminals and inhibit MAO. § Delayed effects - delayed clinical response due to down-regulation of b-adrenoceptors and 5-HT2 receptors - again, fits with delayed clinical effect. o Inhibits other enzymes - leads to side effects § Pharmacokinetics: o Oral absorption. o Short plasma T1/2 but a longer DoA due to inrreversible binding to MAO. o Metabolised in the liver, excreted in the urine. § Unwanted effects: o Atropine-like effects (anti-PNS effects) - but less so than TCAs. o Postural hypotension - common. o Sedation - causes seizures in OD. o Weight gain - possibly excessive. o Hepatotoxicity - hydrazines, rare.

CETP Inhibitors - Cholesterol Ester Transfer Protein

e.g. Torcetrapib :§ CETP converts HDL into LDL and so inhibiting it increases HDL levels. § However, CETP inhibitors lead to lots of unexpected deaths so its use was discontinued. potentially due to increases in BP/ wrong type of HDL o thought to be due to off-target effect (not to do with primary mechanism of drug) o difficult to show clinical usefulness.

What are the two types of Dopamine receptor agonists?

ergot and non-ergot. §Fewer patients can be treated with the dopamine agonists as a mono-therapy with many patients being withdrawn from treatment due to major adverse side effects. § Can be used in combination with L-DOPA. When L-DOPA is becoming less effective, dopamine agonists can be used in combination with L-DOPA.

Calculating ratio of unionised to ionised using rearranged henderson-hasselbalch equation

for acids as pH < pKa , have more unionised. for bases pH < pKa, more ionised. if pH = pKa, have 50/50 split.

How is genotype and phenotype determined?

frequently occurring monogenic variation at >1%. 1) Polygenic control - e.g. Salicylate conjugation with glycine or glucuronic acid. o Several genes act together to give a GAUSSIAN (normal) distribution (cannot discern influences of single genes from the action). o Cannot divide the population into phenotypic groups but - individuals always remain at the same place in the distribution and there may be large differences in individuals at the extremes of the distribution. 2) Monogenic control - e.g. see below. o One gene has a large overriding effect that gives rise to a DISCONTINUOUS (multimodal) distribution. § A bi-modality would suggest that there are 2 phenotypes of individuals. · Genotype = gene sequence encoding for the given characteristics. · Phenotype = manifestation of the genotype. o Determinism of a trait, or phenotype, can be - monogenic, polygenic or polymorphic. o The incidence of the population different from the majority and comprise one of the modes, may be low or high - incidence is low = rare-trait/inborn-error, incidence is high (>1%) = polymorphism. § Rare-trait - succinylcholine hydrolysis by plasma cholinesterases (incidence of low activity is low). § Polymorphism - sulphadimidine N-acetylation by N-acetyltransferase low activity is ~50% in Europeans. · This arises when the alleles to encode a gene from both parents are different resulting in different amounts or a different protein being produced.

polymorphic meaning

frequently occurring monogenic variation at >1%. 1) Polygenic control - e.g. Salicylate conjugation with glycine or glucuronic acid. o Several genes act together to give a GAUSSIAN (normal) distribution (cannot discern influences of single genes from the action). o Cannot divide the population into phenotypic groups but - individuals always remain at the same place in the distribution and there may be large differences in individuals at the extremes of the distribution. 2) Monogenic control - e.g. see below. o One gene has a large overriding effect that gives rise to a DISCONTINUOUS (multimodal) distribution. § A bi-modality would suggest that there are 2 phenotypes of individuals. · Genotype = gene sequence encoding for the given characteristics. · Phenotype = manifestation of the genotype. o Determinism of a trait, or phenotype, can be - monogenic, polygenic or polymorphic. o The incidence of the population different from the majority and comprise one of the modes, may be low or high - incidence is low = rare-trait/inborn-error, incidence is high (>1%) = polymorphism. § Rare-trait - succinylcholine hydrolysis by plasma cholinesterases (incidence of low activity is low). § Polymorphism - sulphadimidine N-acetylation by N-acetyltransferase low activity is ~50% in Europeans. · This arises when the alleles to encode a gene from both parents are different resulting in different amounts or a different protein being produced.

Indirectly Acting SNS Agonist Cocaine: MOA, CNS and CVS effects

i.e. the drugs themselves do not act at the adrenoceptors § Cocaine is an uptake 1 blocker. § CNS effects: o Low doses - euphoria, excitement, increased motor activity. o High doses - activation of CTZ (vomiting centre), CNS depression, respiratory failure, convulsions and death. § CVS effects: o Low doses - tachycardia, vasoconstriction and raised BP. **May result in a psychological dependence syndrome (depression, deterioration of motor performance and learned behaviours after withdrawal), but no evidence for a physical dependence.

Factor 2/4 influencing drug distribution : extracellular binding (plasma-protein binding)

if heavily plasma protein bound, will stay in blood and can't access tissues. hence need to adjust dosage. problem with acidic drugs e.g. aspirin or warfarin. also an issue when taking multiple drugs as one drug may displace other drug from plasma protein and then the drug that is displaced reaches much higher conc that may be dangerous.

What are the actions of antithrombin?

inhibits factors IIa and Xa

MUSCARINIC RECEPTOR ANTAGONISTS - Clinical Use in Parkinsons

is loss of dopaminergic neurones from substantia nigra into striata. D1 receptors are dopamine receptors that respond to dopamine and control fine muscle movement. So try to upregulate D1 receptor to increase sensitivity to the limited dopamine being released. Muscarinic receptors (M4) have suppressive effect on D1 receptor. Block M4R to make D1R more receptive and effective.

What do you understand by the term "cardioselective" β-blockers?

just means b1 selective antagonists (target the beta1 receptors in cardiac tissue.). so well used in CV problems called cardioselective

Mrs. Beryl is a 57-year-old with chronic hypertension and takes oral propranolol twice daily. Doctors recently found that her liver function tests have declined so immediately reduced the dosage of her medication. Which of the following is the best explanation for why her dosage was altered?

liver failure reduces first pass metabolism. Topic Summary: The key to answering this question is to think about the function of the liver when drugs are taken orally. The fact that the drug dosage was lowered suggests a change has occurred to make it more bioavailable (greater levels entering the systemic circulation).

Diuretics - common side effects

loop diuretics and thiazides simliar side effects but loop diuretics more severe. Diuretic Side Effects § Hypovolaemia - loop diuretics and thiazides. § Hyponatraemia - loop diuretics and thiazides. § Hypokalaemia - loop diuretics and thiazides. Na+/K+ exchange. § Metabolic alkalosis - loop diuretics and thiazides. due to chloride ion loss with sodium loss. § Hyperuricaemia - loop diuretics and thiazides. o Loop diuretics have a more powerful effect of all. § Hyperkalaemia - K+-sparing diuretics. Less Na+/K+ exchange. § Metabolic acidosis - carbonic anhydrase inhibitors.

Cocaine: Pharmacodynamics - reuptake inhibition

low-dose cocaine: o MAO-A re-uptake inhibitor (uptake 1). o This can affect re-uptake of - NA, DA or 5-HT. o enhances NA, serotonin, DA-like effects. o Note - this is NOT changing the affinity or efficacy dopamine, just increasing the DA in the synaptic cleft.

Factor 1/4 influencing drug distribution : regional blood flow

more metabolically active tissues --> denser capillary network. depends on exercise as well. e.g. gut gets less when exercising but skeletal muscles get more

tropicamide

muscarinic antagonist. dilates pupil, lens thinner (far accomodation)

Antiviral development for HCV

now more towards nucleoside analogues. Now nearly 100% cure rate. Need to test, cure and prevent transmission. Need vaccine to control spread; we don't have vaccine though.

Acetylcholinesterase is found where? Speed of action? selectivity?

o Found in all cholinergic synapses (peripheral and central) o Very rapid action (hydrolysis; >10 000 reactions per second) o Highly selective for acetylcholine - breaks molecule along that line

Propagation: thrombosis

o Generation of fibrin strands 1.Activated platelets: •Large-scale thrombin production 2.Thrombin: •Factor IIa --> binds to fibrinogen and converts to fibrin strands

Genetic polymorphisms in alcohol metabolism

o Genetic polymorphisms (within Asian population) --> asian flush. o Common variation in enzyme ALDEHYDE dehydrogenase = Alcohol intolerance. o Rarer variation in enzyme ALCOHOL dehydrogenase = Prone to alcoholism.

Alcohol Chronic effects: Endocrine system

o Increased ACTH secretion --> Cushing's-like syndrome. o Decreased testosterone --> gynecomastia.

How do diuretics work?

o Inhibiting the reabsorption of Na+ and Cl- - raising excretion. o Increasing the osmolarity of the tubular fluid - decrease osmotic gradient across the epithelia (i.e. osmotic diuretics).

Metabolism of cannabis

o Liver converts THC --> 11-OH-THC (more potent) (phase 1 metabolite). o GIT excretes 65%. § Much of the THC undergoes enterohepatic recycling due to lipid solubility as just gets reabsorbed in gut again. o Urine excretes 25%. **So: Partly excreted in urine (25%) but mainly into the gut (65%) from which they are reabsorbed, further prolonging their actions. **Poor correlation between plasma cannabinoid concentration and degree of intoxication - doesn't tell how much in fat, how much 11-OH-THC levels and how much enterohepatic recycling.

Where are M1, M2 and M3 muscarinic receptors found?

o M1 - salivary glands, CNS, stomach parietal cells o M2 - heart o M3 - salivary glands, bronchial/visceral SM, sweat glands, eye - they are all GPCR (7TM segments) - M1 and M3 (and M5) (odd) are linked to stimulatory G protein (Gq) to form IP3 and DAG to form PLC (PIP2 --> IP3 + DAG) - M2 and M4 (even) form inhibitory G protein (Gi) to reduce cAMP **§ ODD: M1, M3, M5 - Gq (PIP2 --> IP3 + DAG). ** § EVEN: M2, M4 - GI (cAMP)

Pharmacokinetics of 5-ASA and derivatives

o Mesalazine - does not need to be metabolised and is absorbed by small bowel and colon. § Good at maintaining remission in UC. § Topical 5-ASA is better than topical steroids at inducing UC remission. § Combined topical 5-ASA and oral steroids better at inducing remission than oral 5-ASA alone. o Olsalazine - metabolised by gut flora and absorbed by the colon.

Mesolimbic dopamine system

o Mesolimbic dopamine system - Central 'reward' pathway o Medial forebrain bundle (myelinated fibres) --> Ventral tegmental area → Nucleus Accumbens (VTA) (NAcc) o NAcc → releases Dopamine = Reward (End point for drugs of abuse) o route (ascending order for onset of euphoria): oral < intranasal < IV < inhalational. o classification: narcotic, 'upper', 'downer', miscellaneous

Which enzymes metabolise alcohol?

o Metabolism - only 90% is metabolised, 10% breathed off (excreted): § 85% of metabolism occurs in the liver, 15% occurs in the GIT. ** § Liver metabolism: o Alcohol --> acetaldehyde (toxic) via: § 75% - Alcohol dehydrogenase. § 25% - Mixed function oxidase. o acetaldehyde is then meatbolised by aldehyde dehydrogenase (liver)/ aldehyde oxidase (GIT) --> acetic acid. o Ethanol is uncharged and highly lipid soluble rapidly absorbed from the mucous membranes of the stomach and gut (slowed by food). o It is rapidly distributed throughout the body water (distribution dependent on blood flow to individual tissues) o Substantial fraction is removed from portal vein blood due to first pass hepatic metabolism BUT demonstrates saturation kinetics i.e. Rapid absorption (e.g. empty stomach) High portal vein concnliver enzymes become saturated ethanol escapes into systemic circulation.

Metabolism of alcohol

o Metabolism - only 90% is metabolised, 10% breathed off (excreted): § 85% of metabolism occurs in the liver, 15% occurs in the GIT. § Liver metabolism: o Alcohol --> acetaldehyde (toxic) via: § 75% - Alcohol dehydrogenase. § 25% - Mixed function oxidase. · MFO is most significantly upregulated in chronic alcoholics (only 25% in naïve drinkers). o One high-dose alcohol bolus will saturate the enzymatic system and lead to a higher intoxication as opposed to the same absolute amount of alcohol over say 4 separate doses.

Over the next three months, there were two occasions where Gemma had to withdraw from the field during a match due to breathing difficulties, despite having carried out her normal pre-match preparations. On the first occasion, Gemma had caught a cold so had dosed herself with the strongest over the counter preparation she could find to relieve her symptoms. On the second occasion, Gemma wanted to play despite suffering from a pulled muscle in her shoulder. Just prior to the match, one of her team mates had given her some cream which she had found useful for a similar problem. What class of drug to you think was a common factor in both cases? Why did it exacerbate Gemma's asthma? Should the different routes of administration of the two treatments influence the severity of the bronchoconstriction? 2) Not wishing to have a repeat of this problem, Gemma went to see her GP - what advice do you think he gave her?

o NSAIDS - The inclusion of aspirin or ibruprofen in her OTC cold/flu medication. NSAIDs reduce the production of protective bronchodilator prostanoids by blocking COX activity and thus making more arachidonic acid precursor available for the increased production of bronchoconstrictor leukotrienes. As above, the inclusion of aspirin or ibruprofen in the cream reduced the production of protective bronchodilator prostanoids by blocking COX activity and thus making more arachidonic acid precursor available for the increased production of bronchoconstrictor leukotrienes. It is quite possible for either the trans-dermal application and the oral application to induce bronchoconstriction. *Concepts to discuss: o Dosing - in the end, it is the dose and subsequent concentration that reaches the systemic circulation that will determine the degree of bronchoconstriction. We do not know how much drug from either preparation reached the systemic circulation. when topical - administer less, as only has to be lipophilic to pass into bloodstream. o Lipid solubility - this will massively increase the bioavailability of the trans-dermal preparation o Ionisation/first pass metabolism - this will massively influence absorption from the gut and the amount of drug that escapes into the systemic circulation. Students may discuss the following in relation to the effect of viruses on asthma - It is possible that the viruses which cause upper respiratory tract infections such as colds and flu can exacerbate asthma in their own right. Respiratory viruses interact with host factors to promote recurrent virus-induced wheezing and the development of asthma via a number of mechanisms including increased recruitment of inflammatory cells, promotion of cytokine production, enhancement of allergic inflammation, and augmented airways hyperresponsiveness. In addition, the body's response to the infection can cause bronchial hyperresponsiveness, increased mucus secretion and inflammatory mediator release. These mediators can cause the exacerbation of symptoms. 2) Not all patients with asthma as aspirin sensitive, but there is no foolproof way of identifying those who are, so AVOIDING products containing NSAIDS is wise for all asthmatics. The pathogenesis of AIA has implicated both the lipoxygenase (LO) and the cyclooxygenase (COX) pathways. By inhibiting the COX pathway, aspirin diverts arachidonic acid metabolites to the LO pathway. This also leads to a decrease in the levels of prostaglandin (PG) E2, the anti-inflammatory PG, along with an increase in the synthesis of cysteinyl leukotrienes (LTs). Evidence suggests that patients with AIA have increased activity of LTC4 synthase, the rate-limiting enzyme in the cysteinyl LT synthesis, in their bronchial biopsy specimens, thereby tilting the balance in favor of inflammation. The initial event in AIA appears to be the interruption of the synthesis of PGE2. PGE2 has profound regulatory effects on other inflammatory systems. It reduces LT synthesis by inhibiting 5-LO, inhibits cholinergic transmission, prevents mediator release from mast cells, and prevents ASA-precipitated bronchoconstriction.

pharmacokinetics of tubocurarine

o Naturally occuring 4° ammonium compound (alkaloid) found in S. American plant (arrow poison) o Range of synthetic drugs now available * MOA - COMPETITIVE nachr ANTAGONIST - 70 - 80% block necessary to get paralysis so EP potential is then insufficient * EFFECTS - Tubocurarine --> flaccid paralysis Extrinsic eye muscles (double vision) --> Small muscles of face, limbs, pharynx --> Respiratory muscles * order of recovery is in reverse. *USES - Relaxation of skeletal muscles during surgical operations (= less anaesthetic and procedure is safer) esp. in abdominal surgery - Permit artificial ventilation * N.B. - Actions of NON-depolarising blockers can be reversed by ANTICHOLINESTERASES (so raise endogenous Ach and can overcome competitive tubocurarine) - Neostigmine is an anticholinesterase (2-3 hours lasting) (+ atropine to damp down overstimulation of muscarinic receptors) * PHARMACOKINETICS - Roa = i.V. (Highly charged) - Does NOT cross bbb or placenta - so can be used safely in obsetrics - Duration of paralysis: 1 - 2 hr (long) - Not metabolised - Excretion: 70% urine; 30% bile (care if renal or hepatic function impaired) - hence would take longer to be excreted; hence would use this drug Atracurium (15 min; chem. Unstable) - same mechanism but short half life - is hydrolysed in plasma after 15 mins * UNWANTED EFFECTS: (GANGLION BLOCK; HISTAMINE RELEASE) a) HYPOTENSION •Ganglion blockade (decreases tpr) in other receptors •Histamine release from mast cells - as tubocurarine is so basic; is vasodilator and decreases TPR b) TACHYCARDIA (MAY -->ARRHYTHMIAS) •Reflex to drop in BP •Also from blockade of vagal ganglia c) BRONCHOSPASM - due to histamine release d) EXCESSIVE SECRETIONS (BRONCHIAL & SALIVARY) - due to histamine release e) APNOEA (ALWAYS ASSIST RESPIRATION)

unwanted effects of tubocurarine

o Naturally occuring 4° ammonium compound (alkaloid) found in S. American plant (arrow poison) o Range of synthetic drugs now available * MOA - COMPETITIVE nachr ANTAGONIST - 70 - 80% block necessary to get paralysis so EP potential is then insufficient * EFFECTS - Tubocurarine --> flaccid paralysis Extrinsic eye muscles (double vision) --> Small muscles of face, limbs, pharynx --> Respiratory muscles * order of recovery is in reverse. *USES - Relaxation of skeletal muscles during surgical operations (= less anaesthetic and procedure is safer) esp. in abdominal surgery - Permit artificial ventilation * N.B. - Actions of NON-depolarising blockers can be reversed by ANTICHOLINESTERASES (so raise endogenous Ach and can overcome competitive tubocurarine) - Neostigmine is an anticholinesterase (2-3 hours lasting) (+ atropine to damp down overstimulation of muscarinic receptors) * PHARMACOKINETICS - Roa = i.V. (Highly charged) - Does NOT cross bbb or placenta - so can be used safely in obsetrics - Duration of paralysis: 1 - 2 hr (long) - Not metabolised - Excretion: 70% urine; 30% bile (care if renal or hepatic function impaired) - hence would take longer to be excreted; hence would use this drug Atracurium (15 min; chem. Unstable) - same mechanism but short half life - is hydrolysed in plasma after 15 mins * UNWANTED EFFECTS: (GANGLION BLOCK; HISTAMINE RELEASE) a) HYPOTENSION •Ganglion blockade (decreases tpr) in other receptors •Histamine release from mast cells - as tubocurarine is so basic; is vasodilator and decreases TPR b) TACHYCARDIA (MAY -->ARRHYTHMIAS) •Reflex to drop in BP •Also from blockade of vagal ganglia c) BRONCHOSPASM - due to histamine release d) EXCESSIVE SECRETIONS (BRONCHIAL & SALIVARY) - due to histamine release e) APNOEA (ALWAYS ASSIST RESPIRATION)

Tyramine actions

o TYRAMINE a dietary amino acid found in foods such as cheese, red wine and soy sauce. § Also known as the "cheese reaction". § Tyramine acts as a false neurotransmitter. o This is usually not a problem when the normal mechanisms for degradation of MAO are in place. o We used to prescribe MAO inhibitors as anti-depressants. 1. Weak action at the receptors for NA. 2. Weak inhibitory effect on the uptake 1. 3. Displaces NA from the vesicles. 4. Competes for MAO breakdown so less breakdown of NA. 5. Leakage of NA out of the vesicles. Inhibited MAO means that tyramine administration can then compete with any MAO left and lead to a massive hypertensive crisis when NA build-up is more than usual.

uses of tubocurarine

o Naturally occuring 4° ammonium compound (alkaloid) found in S. American plant (arrow poison) o Range of synthetic drugs now available * MOA - COMPETITIVE nachr ANTAGONIST - 70 - 80% block necessary to get paralysis so EP potential is then insufficient * EFFECTS - Tubocurarine --> flaccid paralysis Extrinsic eye muscles (double vision) --> Small muscles of face, limbs, pharynx --> Respiratory muscles * order of recovery is in reverse. *USES - Relaxation of skeletal muscles during surgical operations (= less anaesthetic and procedure is safer) esp. in abdominal surgery - Permit artificial ventilation * N.B. - Actions of NON-depolarising blockers can be reversed by ANTICHOLINESTERASES (so raise endogenous Ach and can overcome competitive tubocurarine) - Neostigmine is an anticholinesterase (2-3 hours lasting) (+ atropine to damp down overstimulation of muscarinic receptors) * PHARMACOKINETICS - Roa = i.V. (Highly charged) - Does NOT cross bbb or placenta - so can be used safely in obsetrics - Duration of paralysis: 1 - 2 hr (long) - Not metabolised - Excretion: 70% urine; 30% bile (care if renal or hepatic function impaired) - hence would take longer to be excreted; hence would use this drug Atracurium (15 min; chem. Unstable) - same mechanism but short half life - is hydrolysed in plasma after 15 mins * UNWANTED EFFECTS: (GANGLION BLOCK; HISTAMINE RELEASE) a) HYPOTENSION •Ganglion blockade (decreases tpr) in other receptors •Histamine release from mast cells - as tubocurarine is so basic; is vasodilator and decreases TPR b) TACHYCARDIA (MAY -->ARRHYTHMIAS) •Reflex to drop in BP •Also from blockade of vagal ganglia c) BRONCHOSPASM - due to histamine release d) EXCESSIVE SECRETIONS (BRONCHIAL & SALIVARY) - due to histamine release e) APNOEA (ALWAYS ASSIST RESPIRATION)

Non-depolarising NM blocker: tubocurarine mechanism of action

o Naturally occuring 4° ammonium compound (alkaloid) found in S. American plant (arrow poison) o Range of synthetic drugs now available * MOA: - COMPETITIVE nachr ANTAGONIST - 70 - 80% block necessary to get paralysis so EP potential is then insufficient * EFFECTS - Tubocurarine --> flaccid paralysis. - o The flaccid paralysis then affects the muscles in a particular order: Extrinsic eye muscles (double vision) --> Small muscles of face, limbs, pharynx --> Respiratory muscles * order of recovery is in reverse (I.E. eye muscles are blocked first and recover last!) *USES - Relaxation of skeletal muscles during surgical operations (= less anaesthetic and procedure is safer) esp. in abdominal surgery - Permit artificial ventilation * N.B. - Actions of NON-depolarising blockers can be reversed by ANTICHOLINESTERASES (so raise endogenous Ach and can overcome competitive tubocurarine) - Neostigmine is an anticholinesterase (2-3 hours lasting) (+ atropine to damp down overstimulation of muscarinic receptors) * PHARMACOKINETICS - Roa = i.V. (Highly charged) - Does NOT cross bbb or placenta - so can be used safely in obsetrics - Duration of paralysis: 1 - 2 hr (long) - Not metabolised - Excretion: 70% urine; 30% bile (care if renal or hepatic function impaired) - hence would take longer to be excreted; hence would use this drug Atracurium (15 min; chem. Unstable) - same mechanism but short half life - is hydrolysed in plasma after 15 mins * UNWANTED EFFECTS: (GANGLION BLOCK; HISTAMINE RELEASE) a) HYPOTENSION •Ganglion blockade (decreases tpr) in other receptors •Histamine release from mast cells - as tubocurarine is so basic; is vasodilator and decreases TPR b) TACHYCARDIA (MAY -->ARRHYTHMIAS) •Reflex to drop in BP •Also from blockade of vagal ganglia c) BRONCHOSPASM - due to histamine release d) EXCESSIVE SECRETIONS (BRONCHIAL & SALIVARY) - due to histamine release e) APNOEA (ALWAYS ASSIST RESPIRATION)

Nicotine - pharmacodynamics - metabolic

o Nicotine (STIMULANT) leads to an increase in metabolic rate (and decreased appetite). o So, after STOPPING smoking, this can lead to a GAIN in weight (no longer have a faster metabolism).

Monogenic control

o Owing to the action of a single gene that has a large overriding effect. This gives rise to a DISCONTINUOUS or MULTIMODAL distribution of the measured variable. An observed bimodality, for example, would strongly suggest that the population consisted of two types of individual with regard to the property measured. These would be two PHENOTYPES. o The incidence within the population of individuals who are 'different' from the majority, and comprise one of the modes, may be low or high. If the incidence is low the phenomenon is termed a 'rare trait' or 'inborn error', if it is high (above 1%) it is termed a 'polymorphism'. **Example in Drug Metabolism: (a) Rare trait: Ø succinylcholine hydrolysis by plasma cholinesterase (incidence of low enzyme activity is about 0.05-0.025%) (b) Polymorphism: Ø debrisoquine (+ other drugs) hydroxylation by cytochrome P450 2D6 (incidence of low enzyme activity is about 7-10% in Europeans, 1-2% in Orientals) Ø sulphadimidine (+other drugs) N-acetylation by N-acetyltransferase (incidence of low enzyme activity is about 50% in Europeans)

Examples of PPI and H2 receptor antagonist

o PPI - omeprazole. inhibit acid secretion by >90%. o H2 receptor antagonist - ranitidine. inhibit gastric acid secretion by approximately 60% and are less effective at healing ulcers than PPIs

Main contributors to hypertension (3)

o Physiology •Blood pressure (BP) = cardiac output (CO) x total peripheral resistance (TPR) o Main contributors: Blood volume, Cardiac output, Vascular tone

Presentation and investigations of MI

o Presentation: •History of hypertension & hyperlipidaemia •Shortness of breath, sweating, dizziness & chest pain o Investigations: •Blood pressure = 122/83, Pulse rate = 68 bpm, Respiratory rate = 21 breaths per minute, SpO2 = 92% •No changes on ECG & elevated TROPONIN. **NON-ST ELEVATED = NSTEMI o do antiplatelet therapy (aspirin and clopidogrel)

Presentation and investigations for stroke

o Presentation: •Severe headache, dizziness & loss of coordination •Numbness in the face, arms and legs o Investigations: •Serum glucose & electrolytes - within normal ranges •CT scan - eliminate possibility of haemorrhagic stroke. to see if occlusive (more common) or haemmorrhagic (hence got to make sure don't give antiplatelets for haemorrhagic) o Diagnosis & Treatment: •Ischaemic stroke •Thrombolytic therapy --> ALTEPLASE (tPA) (thrombolytics usually only given in emergencies) **thrombus formed in atria of heart, potentially due to atrial fibrillaion --> embolised up to brain and lodged in cerebral artery. lodged in lumen.

Pros and cons of Intramuscular - into connective tissue reservoir in muscle block

o Pro: relatively high blood flow, increased during exercise enables DEPOT THERAPY (prolonged absorption from pellet, microcrystalline suspension or solution in oily vehicle). o Con: possible infection and nerve damage (especially in gluteal region)

Cocaine: Pharmacodynamics - euphoria

o Reduces re-uptake of DA into pre-synaptic neurone so more DA in the NAcc (from the VTA).

Renal failure as S/E of ACEi and ARBs

o Renal failure (in patients with renal artery stenosis) - ACEi, ARBs. o Glomerular filtration is maintained by AngII so you need to be careful in renal failure patients.

Main effects of PNS and SNS on heart

o SNS: a) increased force of contraction (positive inotropic effect) b) increased heart rate (positive chronotropic effect) c) increased automaticity d) repolarization and restoration of function following generalized cardiac depolarization e) reduced cardiac efficiency (i.e. cardiac oxygen consumption is increased more than cardiac work). *These effects are largely due to activation of β1 adrenoceptors. Activation of β1 adrenoceptors stimulates adenyl cyclase resulting in production of cyclic AMP from ATP. This acts as an important intracellular messenger to increase intracellular Ca2+ (probably largely as a result of effects on L-type calcium channels and the sarcoplasmic reticulum) and stimulate Na-K ATPase in cardiac myocytes. O PNS: Activation of the parasympathetic system results in: a) Cardiac slowing and reduced automaticity Inhibition of AV conduction Preload and after-load. b) Cardiac work also depends on the load the heart experiences i.e. venous return (preload) or the impedance of the arterial circulation (after-load).

As well as giving her some advice, the doctor also suggested Gemma had a trial of an additional medication called montelukast. This is a leukotriene antagonist. What is the rationale for using such a drug in asthma and why do you think the doctor is trying it in Gemma's case?

o The bronchoconstriction of asthma is caused by a soup of different mediators, the exact composition of which is unique to each individual patient (and also various in response to environmental factors, like infections - see above). The fact that aspirin caused Gemma to suffer an increase in symptoms suggests that leukotrienes might be significant contributors to her bronchoconstriction so a leukotriene antagonist is worth a try. o Some asthma phenotypes seem particularly sensitive to montelukast, such as asthma predominantly induced by exercise or asthma associated with allergic rhinitis. o It is important to note that whilst LT antagonists have an important role to play in asthma management, the current guidelines recommend inhaled corticosteroids as the first step preventer for most people most of the time and that's largely because they will give blanket reduction of bronchoconstrictor mediators so they are a safe bet.

Opiate structure-activity- Morphine vs Heroin/Codeine:

o The hydroxyl group at position 3 - required for binding.o The tertiary nitrogen also permits receptor anchoring (important in affinity) and aromatic ring. So along that same plane, have hydrogen bonding, van der waal's forces, and bonds between nitrogen and receptor. o Heroine is di-acetyl morphine: morphine with two hydroxyl groups replaced with two acetyl groups. o Codeine is methyl-morphine: methyl instead of hydroxyl. o Codeine is a pro-drug: must undergo some metabolism to become activated and reveal its hydroxyl group. o Heroine is also a pro-drug, because doesn't have hydroxyl group - can't bind to receptor as well as morphine (MORPHINE IS BEST OF THREE AT BINDING) § The hydroxyl group at position 6 - when in oxidised form, the lipophilicity of the drug increases 10-fold. o making the tertiary nitrogen quaternary greatly decrease the analgesia, since it cannot pass into the central nervous system. Changes to the methyl group on the nitrogen will decrease analgesia as well, creating antagonists

Vaughan Williams classification

o Vaughan Williams classification of anti-arrhythmic drugs. § Class 1 - Na+-channel blockade. § Class 2 - b-blockers. § Class 3 - K+-channel blockade - prolong repolarisation. § Class 4 - Ca2+-channel blockade. **This classification is of LIMITED clinical significance due to the significance of cross-overs in rhythm disturbances.

alpha 1 receptor

o a1-receptors •Gq-linked (related to increase in PLC and calcium increase) •Postsynaptic on vascular smooth muscle - increase cell activity o a2-receptors •Gi-linked (increase in cAMP and PKA) •Presynaptic autoreceptors inhibiting NE release - decrease cell activity Clinical pharmacology •Non-selective a-blocker: phentolamine - used to treat phaechromocytoma-induced hypertension •a1 specific blocker: prazosin inhibit the vasoconstrictor activity of NE •Have modest blood pressure lowering effects •Only used as adjunctive treatment

Alcohol Chronic effects: GIT

o acetaldehyde damages gastric mucosa (in proportion to the dose). § Can lead to stomach cancer from acetaldehyde build up. § Acetaldehyde is a CARCINOGENIC. § alcohol causes salivary and gastric acid secretions--> irritant effects - histamine HCl, Stimulation of sensory nerve endings --> Long-term consumption damage to gastric mucosa (+ HCl) = gastric/duodenal ulcers

Pleiotropic effects of statins

o affects inflammation (anti-inflammatory) o platelet activation § Statins can be described to have a pleiotropic effect - both good and bad effects. § Statins have multiple effects not directly related to lowering cholesterol (e.g. anti-inflammatory action).

Give a short account of the pharmacology of β-blockers, explaining why they are effective in the treatment of hypertension, tachycardia and arrhythmia.

o antagonists: high affinity, no efficacy o hypertension: block beta receptors on kidneys, so less renin --> less ATII and less aldosterone --> less Na+ and water reabsorption o tachycardia - block beta 1 receptors on heart --> lowers HR o arrhythmia - could be due to problem with AVN, hence using drug to block b1 receptor here could work; but could also potentially look at calcium channel blocker

Mr MacKenzie is a 65 year old gentleman with a 50 year history of smoking. Following a recent diagnosis of chronic obstructive pulmonary disease (COPD), he has cut down his cigarette smoking, but not given up completely. His GP thinks that an antimuscarinic agent might alleviate some of Mr MacKenzie's feeling of breathlessness, particularly when he smokes. What is the rationale for this?

o antimuscarinic - downplays parasympathetic innervation o will cause bronchodilation **The irritant effect of cigarette smoke activates a variety of receptors and can provoke a vagal response. Parasympathetic NS possess constrictor actions on the airway smooth muscle and would thus act to increase airway resistance via increased contraction of the airway smooth muscle. Giving a muscarinic antagonist may counteract some of this.

Why is adrenaline used in the treatment of allergic reactions and anaphylaxis?

o b2 - broncho dilation o b1 - tachycardia - to increase BP and combat hypotension o a1 - vasoconstriction - also to increase BP and combat hypotension Suppression of histamine mediator release. will also help stomach cramps as it relaxes gut

Opiate structure- activity: methadone and fentanyl

o before used to say that for compound to have an effect, had to look like morphine: tertiary nitrogen, quarternary carbon, phenyl group (morphine rule). o Methadone conforms to the 'Morphine Rule' - tertiary nitrogen, quarternary carbon, phenyl group. o Fentanyl - moving away from the morphine rule has generated even more potent opioids i.e. fentanyl has a tertiary carbon NOT a quarternary carbon. **essentially need nitrogen, hydroxyl group at position 3 and aromatic ring - to help bind receptor

Poor correlation between plasma cannabinoid concentration and degree of intoxication

o brain is also very fatty; Brain 60% lipid content - structural component i.e. not available to be metabolised for energy. o columns show THC, 11-OH-THC (phase 1 metabolite), THC-COOH (phase 2 metabolite) --> see 7/8x increase in brain compared to blood. **o The THC is much more concentrated in the brain matter than in the blood as it is very lipid soluble. o Leads to poor correlation between plasma cannabinoid concentration and degree of intoxication.

Caffeine - pharmacodynamics - euphoria

o caffeine interferes with adenosine (NT) o adenosine acts on dopaminergic neurone and post-synaptically; adenosine suppresses reward pathway o hence caffeine can cause euphoria; most caffeine is taken orally with big delay but mild euphoria may occur.

Link between cannabis and psychosis/schizophrenia

o cannabis THC may cause psychotic effects. § One target is the ACC (Anterior Cingulate Cortex). § ACC is involved in performance monitoring with behavioural adjustment to avoid losses; error detection. o I.E. Driving a car whilst talking to a friend and then it starts raining so you stop talking to focus on the road. § Cannabis causes hypoactivity in the ACC (hence ability to monitor and change behaviour decreases)

Food intake and cannabis

o cannabis stimulates food intake o arcuate nucleus receives all signals and determines output. cannabis affects output systems in lateral hypothalamus § Cannabis has 2 actions on the lateral hypothalamus: 1) Pre-synaptic inhibition of GABA --> increases MCH (Melanin Concentrating Hormone) neuronal activity. 2) Increase orexin production. § CB1 causes incraesed orexin. § This acts to increase hunger.

Diuretics - treatment of HF (+oedema)

o causes reduced CO --> activation of RAAS and SNS to maintain BP. o but issue is causing cardiac remodelling and cause hypertrophy and worsening pressure on heart. o also get congestion as venous pooling. get ankle and pulmonary oedema from fluid leakage into tissues. o loop diuretics reduce sodium load and reduce congestion Loop diuretics: § Acute reduction in congestion. o But will increase renin secretion --> cardiac remodelling. § Chronic use is associated with resistance and RAS activation. o Additional use of K+ sparing diuretics is used to try to stop the rebound activation of RAS.

The table above shows some of the age related changes that could influence Mr E's sensitivity to the beta blocker treatment. Discuss which of these would increase and which would decrease the effectiveness of the beta blocker treatment

o decrease GI blood flow: less absorption and less distribution - decreases effect of drug. o total body water decreased: more concentrated drug - increases effect o liver enzymes decreased: less metabolism, stay in body longer; or if pro-drug maybe less converted to active form - more effective. o lower renal blood flow: less excretion and less active reabsorption - more effective (generally 70-80% of drug excreted in kidneys). also from pharmacodynamic perspective: beta receptors located here so if less blood flow then less effect of drug if lower blood flow. so mixed effect. o lower plasma proteins: less drug binding, less distribution - less effective. o lower cardiac beta adrenoreceptor: less receptive to drug. **potential reasons why the elderly are often less sensitive to the pharmacological effects of beta blockers than younger patients. a. Pharmacodynamic - compliance of vessels decreases with age so the effects of vasodilation and constriction will decrease. b. Pharmacokinetic - decreased liver, renal and heart function, increased body fat (lipophilic drugs are absorbed by the adipocytes) and the fact that elderly people take more drugs.

Impact of the microbiome on the pathology of IBD

o defective interactions between the mucosal immune system and the gut flora. there are 10x more gut bacteria than host cells. o This leads to disrupted innate immunity --> uncontrolled inflammation --> physical damage.

A radioactive-labelled paracetamol mass balance study is conducted to study the distribution and metabolism of paracetamol in the rat. Which of the metabolites you have discussed above would you expect to predominantly find in the; bile urine serum

o differs between animals o bile - glucuronide and glutathione o urine - conjugates (glucuronide sulphate etc.), tiny bit of parent compound if water soluble o serum - the parent drug as usually it's systematically delivered, excreted as soon as it reaches kidneys

Blood alcohol levels with number of drinks

o differs for males and females o safe driving limit <0.08%

Cardiac AP process

o driven by SA Node o mostly CALCIUM mediated depolarisation o repolarising potassium channel *Channels: 1) If - hyperpolarization-activated cyclic nucleotide-gated (HCN) channels; "funny" channels: use cAMP, drive SODIUM entry to initiate depolarisation, activated by hyperpolarisation. 2) Ica (T or L) - Transient T-type Ca++ channel or Long Lasting L-type Ca++ channel: Mediates fast calcium influx. 3) IK - Potassium K+ channels *Phase 4 is the spontaneous depolarization (pacemaker potential) that triggers the AP - HR is constantly reacting.* o Sympathetic NS - ↑ cAMP --> ↑ If & Ica --> increase HR and depolarisations. o Parasympathetic - ↓ cAMP --> ↑ IK. **Cells within the sinoatrial (SA) node are the primary pacemaker site within the heart. These cells are characterized as having no true resting potential, but instead generate regular, spontaneous action potentials. Unlike non-pacemaker action potentials in the heart, and most other cells that elicit action potentials (e.g., nerve cells, muscle cells), the depolarizing current is carried into the cell primarily by relatively SLOW Ca++ currents instead of by fast Na+ currents. There are, in fact, NO FAST Na+ channels and currents operating in SA nodal cells.**

Why is combo therapy good in treating ulcers?

o eliminates bacterial infection whilst also decreasing acid produced from parietal cells in stomach

Biosynthesis of Ach

o enzyme - CAT o degraded by acetylcholinesterase

Why are drugs abused?

o euphoria o dopaminergic system; cell bodies for neurones in VTA --> project to ventral striatum nucleus accumbens and dopamine release here --> euphoria. o also with certain food stuffs and high glucose foods.

Comparison of potency, duration and lipi solubility of opioids

o fentanyl most potent, codeine least o methadone longest acts o fentanyl most lipid soluble o Lipid Solubility: Methadone/Fentanyl >> Heroin > Morphine o Codeine - more lipid soluble than morphine, but less potent due to metabolism o General rule of thumb - More lipid soluble, more potent. **Comparison of potency is complex. What route are you comparing? E.g. oral vs i.v. vs i.m. etc. What effect are you comparing? E.g. euphoria vs analgesia vs respiratory depression.

Treatment steps for deep vein thrombosis

o give LMW heparin first as works quickly (dalteparin) o then do maintenace treatment - rivaroxaban and warfarin o tend not to to use dabigotran as works too well and can cause GI bleeding.

Administration of alcohol

o oral. § Absorption: o 20% from the stomach directly. o 80% from the intestine. § Speed of onset of intoxication >proportional> to gastric emptying. o Post-prandial, the stomach does not empty often as it needs to break down food thus alcohol is not absorbed very well - i.e. eating a meal decreases speed of onset. ** hence speed of onset is proportional to gastric emptying.

Treatment for peptic ulcers when first line treatment doesn't work

o if have chronic stage of disease can switch up antibiotics: •Antibiotics for H Pylori (amoxicillin & clarithromycin/metronidazole). a) Consider quinolone or tetracycline - bismuth, sucralfate (make it less acidic - make it more difficult for bacteria to access and also reduces inflammation of epithelia) b) Proton Pump Inhibitor (omeprazole) - 4-12 weeks * sucralfate -polymer containing aluminium hydroxide and sucrose octa-sulphate. *bismuth - Increases - prostaglandin, mucus and HCO3- production. Decreases - number of H. pylori **These two drugs are cytoprotective - enhance mucosal production mechanisms and/or build a physical barrier over the ulcer.

Effect of remove hydroxyl group at position 6 in morphine

o if remove hydroxyl group at position 6 and replace with something like acetyl group --> compound becomes more lipophilic. § The hydroxyl group at position 6 - when in oxidised form, the lipophilicity of the drug increases 10-fold. o so heroine is most lipid soluble (accesses tissues better) but morphine binds better.

Selected anti-arrythmics: Amiodarone

o in dead tissue of Purkinje fibre, AP can't move down branch 2, doesn't cancel out branch 1 coming out branch 3 and re-entering branch 2 ---> get jerky arrhythmias (full explanation below) **§ Uses - SVT and VT (often due to RE-ENTRY). § MoA - complex but probably involving multiple ion-channel block. Most likely prolongs hyperpolarisation which reduces change of re-entry. o Class 1, 2, 3 and 4 - hence limited clinical importance. **§ Adverse effects: o Accumulation in body (t½ 10 - 100days). o Skin rashes (photosensitive). o Hypo- or hyper-thyroidism. o Pulmonary fibrosis. ***Detailed explanation:** In normal tissue (top panel of figure), if a single Purkinje fiber forms two branches (1 & 2), the action potential will travel down each branch. An electrode (*) in a side branch off of branch 1 would record single, normal action potentials as they are conducted down branch 1 and into the side branch. If branches 1 & 2 are connected together by a common, connecting pathway (branch 3), the action potentials that travel into branch 3 will cancel each other out. Reentry (bottom panel) can occur if branch 2, for example, has a unidirectional block. In such a block, impulses can travel retrograde (from branch 3 into branch 2) but not orthograde. When this condition exists, an action potential will travel down the branch 1, into the common distal path (branch 3), and then travel retrograde through the unidirectional block in branch 2 (blue line). Within the block (gray area), the conduction velocity is reduced because of depolarization. When the action potential exits the block, if it finds the tissue excitable, then the action potential will continue by traveling down (i.e., reenter) the branch 1. If the action potential exits the block in branch 2 and finds the tissue unexcitable (i.e., within its effective refractory period), then the action potential will die. Therefore, timing is critical in that the action potential exiting the block must find excitable tissue in order for that action potential to continue to propagate. If it can re-excite the tissue, a circular (counterclockwise in this case) pathway of high frequency impulses (i.e., a tachyarrhythmia) will become the source of action potentials that spread throughout a region of the heart (e.g., ventricle) or the entire heart. Local sites of reentry may involve only a small region within the ventricle or atrium and can precipitate ventricular or atrial tachyarrhythmias, respectively. Because both timing and refractory state of the tissue are important for reentry to occur, alterations in timing (related to conduction velocity) and refractoriness (related to effective refractory period) can either precipitate reentry or abolish reentry. For this reason, changes in autonomic nerve function can significantly affect reentry mechanisms, either precipitating or terminating reentry. Many antiarrhythmic drugs alter effective refractory period or conduction velocity, and thereby affect reentry mechanisms (hopefully abolish).

Cocaine Pharmacodynamics - CNS: hyperthermia

o in overdose --> increase locomotor activity, agitation, involuntary muscle contraction (HEAT PRODUCTION). o this combined with hot environment --> hyperthermia. mechanisms to help this is increased sweat production, cutaneous vasodilation and altered central threshold for thermoregulation. o Vasoconstriction. o Hyper-pyrexia (fever) --> epilepsy.

What type of channel is nicotinic receptor?

o ion-channel linked; is fastest; hence on pre-ganglionic receptor

Paraceamol overdose may cause...

o irreversible liver failure § If glutathione is depleted (saturated whilst metabolising the other paracetamol molecules), the metabolites oxidise the thiol groups of key hepatic enzymes and cause apoptosis. § overdose can be done as a suicide attempt. § Antidote: o Add a compound with an -SH group. 1) IV Acetylcysteine - used in cases of attempted suicide. · If not administered early enough, liver failure may be unpreventable. 2) Oral methionine.

Pharmacokinetics of infliximab

o is antibody ØInfliximab given intravenously ØVery long half-life (9.5 days) ØMost patients relapse after 8 - 12 weeks ØTherefore repeat infusion every 8 weeks

Alcohol Acute effects: Euphoria

o like opiate o § Alcohol binds to the gabba-receptor to inhibit GABA release. § Less inhibitory GABA means less inhibition on DA release by the VTA DA neurones into the NAc

One month after starting the statin and the beta blocker, Mr E's partner brings Mr E to see you in clinic. Apparently Mr E has been very confused recently, he keeps repeating himself and often struggles to remember simple things. Discuss possible reasons for Mr E's acute confusional state (delirium)

o lipid soluble so can cross the BBB and affect CNS. o dehydration. o hypotension, hyponatremia, hypokalaemia. o he's polypharmacy - 9 drugs

Nicotine: pharmacodynamics - euphoria

o nAChRs are found on the soma of the dopamine nuclei in the VTA. o Stimulation of these receptors stimulates DA release in the NAcc. o directly stimulates nerve through activation of nAChR

Biosynthesis of NA

o need 3 different enzymes (TH, DD, DBH) o 2 uptakes and degradation productions (COMT in effector cell, MAO-A in presynaptic) **•Tyrosine hydroxylase •DOPA decarboxylase •Dopamine beta hydroxylase •MAO-A (monoamine oxidase) - neuronal tissue •COMT (Catechol-O-Methyl Transferase) - extraneuronal tissue

NMDA receptor

o normally blocked by Mg2+. After glutamate and glycine bind and Mg2+ detached, it opens --> calcium and sodium influx. o a specialized ionotropic glutamate receptor that controls a calcium channel that is normally blocked by Mg2+ ions; involved in long-term potentiation. A receptor site on the hippocampus that influences the flow of information between neurons by controlling the initiation of long-term potentiation. o a glutamate receptor that also binds the glutamate agonist NMDA and that is both ligand-gated and voltage-sensitive

Azathioprine and Crohn's Disease

o not really used in UC Ø Not recommended for active disease Ø Azathioprine or other immunosuppressants recommended for maintaining REMISSION Ø Glucocorticoid-sparing (can reduce GC by giving azathioprine) Ø Slow onset - 3 to 4 months treatment for clinical benefit Ø If ineffective move to biological therapies (more potent)

endogenous mediators which are found in the human respiratory tract

o number of which can modulate airways diameter. The most widely studied of these are the leukotrienes, some prostaglandins, bradykinin and histamine.

Proximal tubule cell

o permeable to water and sodium from lumen o Na/K ATPase to absorb sodium and maintains conc gradient o no protein in lumen, but much protein in blood, hence there's oncotic pressure along kidney to draw water into cell o water can move into cell via aquaporins or can go paracellularly if gap big enough. § Sodium is taken up and co-transports the H2O. o 65-70% of Na+ reabsorbed. § There are lots of basal Na+/K+-ATPases to retain the sodium gradient. § Oncotic pressure is assisted by the movement of proteins and sodium.

Vascular tone/peripheral vascular resistance

o pic shows factor affecting peripheral. o resistance and tone. The contractile state of vascular smooth muscle regulates the diameter of arteries and veins and influences blood flow, blood pressure and venous return. The contractile state of vascularsmooth muscle is controlled by a variety of neural, circulating and local factors (see fig 1). § The sympathetic nerve has varicosities along its length and these primarily release NA to stimulate vasoconstriction. § VSM mediators that can increase [Ca2+] and stimulate a VSM contraction include: o AngII --> AT1r o PGG2, PGH2 --> TP (T-prostanoid receptor). o ET1 --> ETA/B o NA o ATP § Endothelial cell agonists that can stimulate a relaxation from an increase in [Ca2+] include: o NO. o CNP - C-Type Naturietic Peptide. o PGI2. o EDHF - Endothelial Hypopolarising Factor. *prostaglandins can cause both contraction or relaxation depending on prostaglandin. § BP is generally mediated by CO and TPR (BP =CO x TPR).

History of cocaine

o plant-based compount (Erythroxylum coca is plant) o is an alkaloid o been around since 6th century; first discovered by peruvian indians. o is a STIMULANT (opposite to alcohol and cannabis). o originally sold as 'brain elixir' and found in coca cola. § Cocaine / Erythroxylum coca - leaves contain 0.6-1.8% cocaine. § Cocaine sulphate ('paste') - § Extracted using an organic solvent. Impure!: a) Cocaine HCl - Passed through an acidic aqueous solution (HCl); the solution is neutralized and the cocaine is extracted by recrystallization. b) Cocaine freebase - Dissolve cocaine HCl in water and precipitate out cocaine using an alkaline solution (e.g. sodium bicarbonate). Then dissolve in a non-polar solvent e.g. diethyl ether. Crack - As for freebase, but do not dissolve in non-polar solvent.

What is the advantage of atenolol over propranolol?

o propanolol - Non-selective. 'Equal' affinity for b1 & b2 receptors o atenolol - b1-selective. more selective for b1 receptors. o less likely for asthmatic and diabetics to have issues as is only b1 selective **•Beta 1 selective - Historically called cardio-selective drugs. •b1-Selective, antagonises the effects of noradrenaline on the heart but will affect any tissue with b1 receptors e.g. Kidney. •Less effect on airways than non-selective drugs, but still not safe with asthmatic patients. It still has some B2 activtiy. Selectivity is concentration dependent. •CANT USE PROPANOLOL with asthmatics

What advantage does carvedilol have over atenolol and propranolol?

o propanolol - Non-selective. 'Equal' affinity for b1 & b2 receptors o atenolol - b1-selective. more selective for b1 receptors. o carvediol - Mixed b- a blockers. a1 blockade gives additional vasodilator properties * get more powerful hypotensive effect. not only beta mediated effects on heart (b1) and kidney (b2) and also arterioles (a1) **•It is a dual-acting β1 and α1-antagonist with a ratio of 4:1 (β1:α1) •This drug lowers blood pressure via a reduction in peripheral resistance and decrease in renin secretion. Like b-blockers, carvedilol, induces a change in heart rate or cardiac output but this effect wanes with chronic use

explain the most likely reason why ritonavir must be taken with meals.

o protect stomach from damage and irritation and reduced nausea. o takes time to digest meal so more time to absorb drug

What is psychoses classified into?

o psychoses - "severe mental disorders, with or without organic damage, characterised by derangement of personality and loss of contact with reality and causing deterioration of normal social functioning." o split into schizophrenia and affective disorders. out of affective disorders there is mania and depression. **Symptoms: §Emotional/Psychological - misery, apathy, pessimism, low self-esteem, loss of motivation, anhedonia (loss of enjoyment from activities). §Biological/Somatic - slowing of action/thoughts, loss of libido, loss of appetite, sleep disturbances.

PCSK9

o secreted by cells. § PCSK9 is an inhibitor of the LDL receptor. o LDLR and PCSK9 gene expression are coinduced by statins o hence, PCSK9 inhibition enhances the lipid-lowering effects of statins § Monoclonal anti-PCSK9 antibodies have been made to inactivate PCSK9 and so more LDL can be absorbed by the liver. § One such group of patients that benefits from PCSK9 inhibition greatly are the people with Familial Hypercholesterolemia (FH)!!. o approved in UK and USA BUT EXPENSIVE: £4000 or $14,000/ year o mainly for people with FH. o recently developed a VACCINE against PCSK9 (inclisiran) - given S/c twice a year. more convenient and maybe cheaper. not yet licensed.

Mild-moderate effects vs severe effects of cocaine

o severe effects with high/ chronic doses o positive/reinforcing --> negative/stereotyping o often dose-related: § o Acute-use - mild-moderate effects: § There are initially positively reinforcing effects such as mood amplification and heightened energy but this flips to... o Chronic use - severe effects: § Chronic higher-dose users tend to then to start to exhibit severe effects such as total insomnia and decreased libido.

Explain the difference between a "single blind, non-crossover trial" and a "double blind crossover trial". List the advantages and disadvantages of each one.

o single blind - volunteers don't know but operators know (risk of experimental bias). double blind - volunteers and operators don't know. o non-crossover - don't crossover placebo and drug. crossover- do it once, have washover period then swap and see - pro: each person acts as their own control for placebo and drug. could use less people; the wash-out period might affect cohort size after, if drug A has marked effect they may think that they're getting placebo this time round - so anticipation could affect

Environmental risk factors for IBD

o smoking (CD especially), medication and diet - strong evidence. o this might affect microbiome causing IBD or might be microbiome causing the effect itself (chicken or egg?)

Cannabis is very lipid soluble... what does this mean?

o so if inhale --> blood --> any tissue it reaches --> diffuses into. hence, the amount that enters tissue depends on blood flow to the tissue. o with chronic cannabis use, get huge accumulation in perfused fatty tissue. 10^4:1 (fatty tissue: plasma). o it is still reversible though, cannabis will slowly leak from fatty tissue to blood. § Cannabis slowly accumulates in the body as it is very lipid soluble (builds up as fatty acid conjugates). o Takes 30 days for effects to cease on the body. § Metabolism: o Liver converts THC --> major metabolite 11-OH-THC (11-hydroxy-THC) (more potent cannabinoid itself). o GIT excretes 65%. § Much of the THC undergoes enterohepatic recycling due to lipid solubility. o Urine excretes 25% **So: Partly excreted in urine (25%) but mainly into the gut (65%) from which they are reabsorbed, further prolonging their actions.

How would you expect cocaine to influence sweat production and cutaneous vasodilation?

o sweat and cutaneous vasodilation actually related to Ach more than NA. o cocaine helps with NA though. o Cocaine inhibits cutaneous vasodilation and enhances sweat production. o cocaine elevates the threshold for sweating/cutaneous vasodilation threefold. *cocaine hence acc increases body heat production and interferes with body's sweating/cutaneous vasodilation --> hyperthermia * main thing is to REMOVE YOURSELF FROM HOT ENVIRONMENT

Aminosalicylates

o symptomatic treatment for IBD: mesalazine (aka 5- ASA) or Olsalazine. § Treatment: o Ulcerative colitis - first line in inducing and maintaining REMISSION with a good evidence base. also low side effects and is safe. o Crohn's disease - non-effective in active disease but may help maintain surgically-induced remission. § General information: o Mesalazine (5-aminosalicyclic acid / 5-ASA). § Olsalazine (2 linked 5-ASA molecules). o These are anti-inflammatory drugs. § Mechanisms of action: o Inhibition of IL-1, TNF-a and PAF (Platelet Activating Factor). o Decrease antibody secretion. o Non-specific cytokine inhibition. o Reduce cell migration - macrophages. o Localised inhibition of immune responses. § Pharmacokinetics of 5-ASA and derivatives: o Mesalazine - does not need to be metabolised and is absorbed by small bowel and colon. § Good at maintaining remission in UC. § Topical 5-ASA is better than topical steroids at inducing UC remission. § Combined topical 5-ASA and oral steroids better at inducing remission than oral 5-ASA alone. o Olsalazine - metabolised by gut flora and absorbed by the colon.

Genotyping by electrophoresis

o the five family members also donated a DNA sample which permits determination of the NAT (n-acetyltransferase) genotype. o the NAT genotype may be present as: 1) wild-type (fast acetylator phenotype) 2) M1/M1 polymorphism (slow acetylator phenotype) 3) heterozygous M1/ wild type o M1 variant differs from the wild-type allele by a substitution of T to G at nucleotide 1098. o introduces a new Mboll restriction site, which can be detected by PCR amplification of the allelic sequence and treatment with the Mboll restriction enzyme to determine whether or not DNA can be cleaved. *L - ladder- different lengths of synthetic DNA - used as standard. Wild type - 1 band, no restriction side. M1 polymorphism - has restriction site so 2 bands. If have WT and M1 (heterozygous) then have 3 bands. o father - heterozygous, fast phenotype o mother- heterozygous, fast phenotype o son - heterozygous, fast phenotype o eldest daughter - homozygous slow, slow phenotype o youngest daughter - homozygous fast - fast phenotype

Is it possible to overdose on cannabis?

o the medulla has a LOW CB1R expression and this means that the cardio-respiratory centre is not affected much so it is impossible to overdose on cannabis. hence safer than alcohol which does affect Cardiorespiratory centre.

The following diagram shows how the plasma concentration of drug X changes over time. What is represented by the range indicated by B? efficacy/ apparent volume of distribution/ affinity therapeutic window/ potency of drug

o therapeutic window - range of drug dosages which can treat a disease effectively without having toxic effects. o not efficacy: ability of drug to induce a response in a receptor after binding. can't assess from this graph. o not apparent volume of distribution - pattern of distribution. can't assess from this graph. Topic Summary: The diagram also has labelled the threshold for Adverse drug reactions-above this concentration the patient will experience toxic side effects.

Fatty acid amide hydrolase inhibitor for chronic pain?

o these are key for generating anadamide o so don't just give drugs that target receptors but increase endogenous production of cannabinoids

Diuretics - treatment

o thiazides are 1st line treatment in most countries. o o Thiazides are especially useful in salt-sensitive hypertension. § Thiazides > calcium channel blockers > ACEi - for treating high SBP. o depends on age and ethnicity. § Response: o Initial (4-6 weeks) - reduction of BP due to reduction of blood volume. o After 4-6 weeks - plasma volume restored due to tolerance. o Chronic thiazides - reduction of TPR due to - activation of eNOS, Ca2+-channel antagonism and opening of KCa-channels. Leads to... § NO production, less calcium influx and hyperpolarisation.

what is triple therapy for hypertension? Mr E is on standard triple therapy and cannot tolerate spironolactone or high-dose diuretic therapy. What further anti-hypertensive medication would you use?

o triple therapy: CCB, ACEi and thiazide-like diuretic. o can't have spironolactone so has to have alpha or beta blocker. o use beta blocker: as alpha blocker has worse side effect profile, beta blockers are more effective.

PCT cross-section

o tubular cells circular o villi and microvilli o capillaries

Selected anti-arrythmics: Digoxin (cardiac glycosides)

o used for atrial fibrillation and atrial flutter mainly. § MoA - inhibits Na+/K+ ATPase --> increased intracellular sodium --> reversal of Na+/Ca2+ exchanger --> sodium effluxed and calcium influx --> increased intracellular calcium. o Increased intracellular calcium lengthens the class IV area of the ventricular muscle graph so LOWER chronicity. o However, INCREASED ionotropic (contractility) effect as more calcium inside the cells. § MoA - central vagal stimulation (parasympathetic effects)--> increased refractory period + reduced rate of conduction through AV-node - improves rhythym control by decreasing chronotropy AND also improving CO by improving inotropy. § Uses - atrial fibrillation and flutter lead to rapid ventricular rate which impairs ventricular filling (due to decreased filling time) and reduce CO --> digoxin via vagal stimulation reduces conduction within AV node and so fewer impulses get to ventricles, slowing down ventricular tachyarrhythmia (VT) § Side effects - dysrhythmias - e.g. AV-conduction block, ectopic pacemaker activity **Note - if co-administered with diuretics (maybe to reduce BP), hypokalaemia may be present and can LOWER the threshold for digoxin toxicity - digoxin is a K+-receptor competitive antagonist and so low blood potassium means less competition and so the effects of digoxin are enhanced.

Alcohol Chronic effects: CNS

o with chronic alcohol, thiamine is reduced - alcoholics get a lot of calories from alcohol and hence they don't get enough thiamine in diet --> thiamine deficient. thiamine important as co-factor for metabolic reactions in brain. o Brain regions with high metabolic demand - impaired metabolism, NMDA excitotoxicity, ROS (reactive oxygen species). 1) Dementia - Cortical atrophy/ decreased volume cerebral white matter confusion (encephalopathy), oculomotor symptoms. 2) Ataxia - Cerebellar cortex degeneration - gait 3) Wernicke-Korsakoff syndrome (due to thiamine deficiency): a) Wernicke's encephalopathy - (hypothalamus/thalamus)- affects the 3rd ventricle and aqueduct. § Reversible. b) Korsakoff's psychosis - (deep brain e.g. hippocampus)- affects the dorsomedial thalamus (impairs memory (they make memories up)). § Irreversible.

The following graph shows the increase in the plasma concentration of three different statins (pravastatin, atorvastatin and simvastatin) after co-administration with ritonavir. Interpret the graph and explain how ritonavir is influencing the plasma statin concentration in each case.

o with ritonavir causes simvastatin to increase 3000% and atorvastatin to increase 350% which is too much so too high statin conc - ritonavir reduces metabolism of these statins - CP450 is inhibited as ritonavir is a protease inhibitor. o with pravastatin it reduces but is easier to monitor - different metabolism to other two statins **a. Pravastatin/ritonavir - decreases plasma concentration. i. Ritonavir blocks cytochrome p450 enzymes BUT pravastatin can be metabolised by another route and is cleared in the urine (2-hour half-life). b. Atorvastatin/ritonavir - increases plasma concentration by 400%. c. Simvastatin/ritonavir - increases plasma concentration by 4000%. i. Ritonavir blocks CytoP450 and so statins remain high in the body and are cleared in the faeces (14-hour half life). Simvastatin has a higher percent-increase due to lower bioavailability to begin with.

Selected anti-arrythmics: Adenosine

oAdenosine - used to treat supraventricular arrhythmias. o popular because short-lived and immediate effect. short-lived side effects **Adenosine: § MoA - activates A1 receptors in the SA and AV nodes --> GI protein activation to reduce AC conversion of ATP to cAMP --> decreased cAMP --> decreased ionotropic and chronotropic effect (decreases If, gives tissue longer time to repolarise). **Uses: •Used intravenously to terminate supraventricular tachyarrhythmias (SVT). Its actions are short-lived (20-30s) and it is consequently safer than verapamil. § also promotes relaxation of vascular smooth muscle, vasodilation --> reduces work on heart too.

Biosynthesis of general NT

precursor, transmitter, vesicle packaging, calcium influx, exocytosis, travels across, binds to post-synaptic receptor, degradation products

What is an Anxiolytic?

remove anxiety without impairing mental or physical activity ("minor tranquillisers"). 'Major tranquilisers' are anti-psychotic. *Ideally: they should: I) have wide margin of safety Ii) Not depress respiration Iii) Produce natural sleep (hypnotics) Iv) Not interact with other drugs V) not produce 'hangovers' Vi) Not produce dependence. **these drugs in pic can have overlapping effects when vary the drug doses

How many people affected by Parkinsons?

§ 1-2% of individuals over 60 years old (major risk factor is age) § Genetic risk: Around 5% of cases are due to mutations in certain genes (e.g. SNCA, LRRK2) - link to early-onset Parkinson's. § 1 in 1000 general population, 1 in 100 of those aged 60 and over. o Mean age of onset is 65 years but can affect younger people. § 4: 1 in males: females - affects 4x as many men. § Causes: o Familial cases of Parkinson's accounts for ~8% of cases - higher chance of onset in a young age. o Idiopathic (unsure of sporadic causes) cases account for ~92% of all cases. § Affects around 100,000 but affects less than Alzheimer's, epilepsy and stroke.

Antiretrovirals for HIV categories

§ 20 years ago there was only one drug approved for the treatment of HIV,ZIDOVUDINE (aka AZT) and now there are around 20 'antiretrovirals' regularly used. The development of these drugs have revolutionised treatment of HIV and patients can now live full lives if the condition is not too advanced. However, patients must have sustained drug therapy for their entire lifetime. The antiretrovirals can be generally separated into five different categories depending on their modes of action. 1) The majority of the early drugs fell into the category of nucleoside reverse transcriptase inhibitors (nRTIs), which all targeted the HIV reverse transcriptase enzyme. 2) The protease inhibitors were the next to be developed, which prevent the HIV proteases from cleaving the emerging proteins required for development of a mature virion. 3) The non-nucleotide RT inhibitors (nnRTIs) were also developed soon after. These also inhibit RT activity but generally use allosteric inhibition of the enzyme. 4) Most recently antiretrovirals have been approved that targets different areas such as HIV entry into a cell. 5) And HIV integration with the host DNA. Depending on individuals' needs, circumstances and tolerance the international AIDS society recommends once daily treatment with a combination antiretroviral agent, known as highly-active antiretroviral therapy (HAART)

What is a peptic ulcer?

§ A peptic ulcer = an area of damage to the inner lining of the stomach (gastric ulcer) or the upper part of the duodenum (duodenal ulcer). o These ulcers can be distinguished based on timing of symptoms: § Gastric ulcer - pain at mealtimes when the acid is secreted. § Duodenal ulcer - pain relieved by a meal as the pyloric sphincter closes (pain starts after 2-3 hours). o Duodenal: Gastric ulcers = 4: 1.

Schematic diagram of ANS - NTs in pre and post ganglionic neurones in parasympathetic vs sympathetic NS

§ ALL pre-ganglionic fibres release ACh regardless of type. § Para-sympathetic NS: o Has LONG pre-ganglionic fibres and SHORT post. o ALL transmitters are ACh. o Is DISCRETE - 1:1 pre- vs. post-. § Sympathetic NS: o Has SHORT pre-ganglionic fibres and LONG post. o Releases mainly A and NA. o Is DIVERGENT (mass discharge) - 1:20 pre- vs. post-.

Diuretics - Thiazides - Bendroflumethiazide:

§ Act on the early DCT. § Inhibit the Na+/Cl—co-transporter --> reducing sodium chloride re-uptake § Not as strong as loop diuretics - 5-10%; not affecting countercurrent that much § Results in K+ and Mg2+ loss and Ca2+ re-absorption (via an unknown mechanism). o Na+ may not be lost but exchanged in the late DCT with potassium so K is lost a) Action on Na+ reabsorption: Inhibit Na+ and Cl- reabsorption in early distil tubule - 5-10%. b) Action on H20 reabsorption: tubular fluid osmolarity = ¯ H2O reabsorption in the collecting duct. c) Other effects: delivery of Na+ to distal tubule K+ loss ( Na+/K+ exchange) - in common with thiazides. d) Mg2+ loss and Ca2+ reabsorption (unknown)

Loop diuretics e.g. frusemide

§ Acts on the ascending limb of the LoH. § Loop diuretics are strong diuretics - 15-30%. § Inhibit the triple transporter (Na, Cl, K) o Impacts the countercurrent effect and ability to concentrate interstitium so don't reabsorb water well from CD. § Results in K+ and Na+ loss as well as loss of Ca2+ and Mg2+. o There is a small leak of potassium into the tubule from the cell physiologically and furosemide inhibits this --> less positive charge luminal pressure --> less paracellular transport of ions. o Mg2+ and Ca2+ ion loss due to loss of K+ recycling. a) Action on Na+ reabsorption: Inhibit Na+ and Cl- reabsorption in ascending limb - 30% b) Action on H20 reabsorption: tubular fluid osmolarity/ ¯ osmolarity of medullary interstitium = ¯ H2O reabsorption in the collecting duct. c) Other effects: delivery of Na+ to distal tubule K+ loss ( Na+/K+) exchange) as send more sodium to later parts of kidney and as transported via Na/KATPase, lose potassium- in common with thiazides d) Ca2+ & Mg2+ - Loss of K+ recycling

Side effects of L-DOPA

§ Acute Side Effects 1) Nausea - Can be prevented by using Domperidone, a peripherally acting dopamine antagonist. 2) Hypotension. 3) Psychological effects - Schizophrenia like syndrome with delusions and hallucinations, 20% of patients also exhibit confusion, disorientation, insomnia and nightmares. **After 6 years of therapy: § Chronic long-term Side Effects 1) Dyskinesias - Abnormal movements which affect the face & limbs. Generally occur within two years of starting L-DOPA therapy. Dyskinesias disappear if the dose of the drug is reduced but clinical symptoms of PD reappear. 2) "On-Off" Effects - rapid fluctuations in clinical state, where hypokinesia and rigidity may suddenly worsen. These "off" periods may last from a few minutes to hours, with sudden improvement in the clinical state. Occurs more with L-DOPA

Administration of nicotine

§ Administration: o Again, short lasting action and a fast reduction in plasma concentration of nicotine leads to addiction. o cigarette is fast, intranasal less fast, gum/inhaler/tablet and patch less fast. o as cigarette is fast onset, is more addictive. § Metabolism: o Nicotine T1/2 = 1-4 hours. o Hepatic CYP-2A6 metabolises 70-80% --> cotinine. o Cotinine is not active and rapidly cleared.

Advantages of BDZs

§ Advantages of BDZs: o Wide therapeutic window - overdose --> prolonged sleep. § Flumazenil is a BDZ antagonist and can reverse effect. o Mild effect on REM sleep. o Does NOT induce liver enzymes.

Epidemiology of ADRs

§ Adverse drug events - preventable or unpredicted medication events with harm to the patient. o Medication errors AND adverse drug reactions. § Epidemiology of ADRs: o 4th-6th leading cause of death amongst patients. o 6.7% incidence of serious ADRs. o 0.3%-7% of all hospital admissions and costs a lot of money. o 30-60% are preventable.

Stages of atherosclerosis

§ Atherosclerosis - an inflammatory fibro-proliferative disorder MOSTLY. 1. LDL enters endothelium (into tunica intima (media is VSMCs)). 2. LDLs are oxidised by macrophages and VSMCs. 3. Release of growth factors and cytokines. 4. Additional monocytes/macrophages recruited. 5. Foam cell accumulation (macrophages that contain a lot of lipid (cholesterol or cholesterol esters). 6. VSMC migration. 7. VSMC proliferation. 8. Plaque growth. **This process does not always occur.

On the same night, an 18-year-old boy smokes several cannabis cigarettes in addition to drinking half a bottle of vodka. Over the course of the night, his motor skills deteriorate and he is eventually helped home to bed by a couple of friends. After administration, describe the different routes that the two drugs took in order to influence the brain.

§ Alcohol - administered via the oral route. Alcohol could be partly absorbed from the stomach, but the majority would be absorbed from the small intestine. Alcohol would cross the plasma membrane of the gut wall and enter the hepatic portal system that returns blood to the liver. Blood would pass through the liver (undergoing some degree of 1st pass metabolism) and leave via the hepatic veins, before flowing into the larger veins and being returned to the heart. Firstly, the alcohol would enter the pulmonary circulation via the right side of the heart, before being returned to the heart and finally would enter the systemic circulation via the left side of the heart and be sent up to the brain. § Cannabis - administered via inhalation. Cannabis would diffuse across the alveoli and enter the pulmonary capillaries and from there would return to the left side of the heart via the pulmonary veins. The left side of the heart would eject the cannabis into the systemic circulation and up into the brain.

Alcohol Acute effects: CNS

§ Alcohol affects the: o Corpus callosum - information from left --> right (impulsivity) o Hypothalamus - controls appetite, emotions, pain, temperature. o RAS - consciousness. o Hippocampus - memory. o Cerebellum - movement & coordination. o Basal ganglia - perception of time

Kidney Physiology - (Late DCT) Collecting Duct:

§ Aldosterone induces Na+-channel production (v aldosterene sensitive) and Na/K ATPase. § VP induces AQA2 synthesis dependant on blood osmolarity. o AQA3/4 constitutively expressed on basal membrane. § Impermeable to free water re-uptake - osmolarity increases as you pass deeper into the medulla so any free absorption would ruin the gradient as water would pass back into the tubular fluid.

The temazepam is withdrawn immediately, but Mr Jones medication is otherwise unchanged. The following year he becomes depressed and his appetite deteriorates. He loses nearly 10 kg in weight but (perhaps unsurprisingly) is reluctant to consider antidepressants. It is noticed that his INR has increased significantly, even though his warfarin treatment is unchanged. Why might this be happening?

§ Although this is somewhat controversial the general view is that the metabolism of many drugs is affected by malnutrition, such as seen here. The end results as far as warfarin is concerned is similar to giving a drug which inhibits the cytochrome pathway. Some experts believe that effect is negligible except in extreme cases. § Malnutrition - particularly protein maltnutrition has been shown to decrease plasma proteins (warfarin heavily plasma protein bound), decrease oxidative metabolism (warfarin is metabolised by oxidation) and decreased GFR.

Why are aminosalicylates better to use chronically to maintain remission in IBD?

§ Aminosalicylates have fewer anti-inflammatory actions than GCs and no immunosuppressive effects and because of this, they are safer to use chronically for the maintenance of remission. § They reduce the recruitment of inflammatory leukocytes and reduce the production of a number of inflammatory mediators. § Aminosalicylates in current clinical use include Sulfasalazine, Mesalazine, Olsalazine. § Except for 5-ASA given alone, all these derivatives are activated by the gut flora. § It is therefore possible to control the site of absorption by modifying the route of drug administration and the exact formulation of the drug. You should know about the sorts of modifications which can be made to target the drugs to different parts of the GIT. § Aminosalicylates are the FIRST LINE treatment for ulcerative colitis.

How to opioids modulate pain?

§ Analgesic effects are mediated by: o Decreased pain perception. o Increased pain tolerance. o Central pain perception? § Mechanism: o Sensory from the periphery nociceptors ---> spinal cord --> into the thalamus via the spinothalamic tract --> cortex. o Thalamus and extra-cortical and cortical inputs activate the PAG (co-ordinates pain; integrating centre for pain tolerance; cortex modulates and sees whether need to increase or decrease pain tolerance). o PAG activates the NRM (Nucleus Raphe Magnus --> signals back down spinal cord to periphery to interfere signal coming up spinal cord). o NRM sends inhibitory descending signals to the dorsal horn - NRM increases pain tolerance. § NPRG (Nucleus Reticularis Paragigantocellularis): o The negative-feedback centre of the brain. o Independent of the thalamus. o This automatically supresses pain before the brain has had a chance to process it. § Hypothalamus: o Constantly signals PAG independent of pain sensation. o samples current state of health and signals you're good/bad to the PAG. § LC (Locus Coeruleus) - major SNS outflow of brain: o Activated during a stress response. o During fight/flight, you do NOT want the pain response interfering with fight/flight. o Pain worse after an accident than during! o so suppresses pain during fight/flight response **in pic: green = pain perception; pink = pain tolerance

Risk vs benefit of NSAID use

§ Analgesic use: o Usually occasionally so relatively low risk of side effects. § Anti-inflammatory use: o Used chronically in higher doses so a relatively high risk of side effects. o also tend to be older patients who can't metabolise as well.

Promethazine

§ Antiemetic used mainly prophylactically for motion sickness - but some benefit may be gained if it is taken after the onset of nausea and vomiting. § UNWANTED EFFECTS: Dizziness, Tinnitus, Fatigue, Sedation ('do not drive or operate machinery'), Excitation in excess, Convulsions (children more susceptible), Antimuscarininc side-effects. § PHARMACOKINETIC CONSIDERATIONS Administer orally. Onset of action 1-2 hours. Maximum effect circa 4 hours. Duration of action 24 hours.

Kidney physiology - ascending limb cell

§ Ascending limb: o Impermeable to water - for countercurrent flow. o Triple transporter (Na, Cl, K) re-absorbs ions. (potassium leaks back slightly). o Na/KATPase maintaining gradient. K/Cl channel. § Na+ is also reabsorbed para-cellularly. § This generates the hypertonic interstitium

Where is aspirin preferentially absorbed? pka = 3.5

§ Aspirin has a pKa of 3.5 and so is preferentially absorbed in any environment with a pH lower than this (so that the drug is in its unionised form). So in the stomach, aspirin is readily absorbed but in the intestine, absorption will be slower. § Enteric-coated aspirin would therefore be advantageous to take if you wanted to either have slow release aspirin or have pain relief of the late GI tract.

Aspirin and Reye's syndrome

ØPatients under 20 ØViral infection and aspirin ØDamage to mitochondria leading to ammonia production resulting in damage to astrocytes - oedema in brain

Principles of anticonvulsant therapy

§ Attempt to achieve control with one drug in view of the many adverse effects and interactions. § Try to ensure accurate information from patient/family on frequency of fits if these persist. § Use therapeutic drug monitoring where available and useful. Usually to check compliance and in suspected toxicity. Phenytoin is the only drug with a well-established therapeutic range. For most drugs, the correct dose is the minimum dose that adequately controls the seizures without intolerable side effects. § Always think about possible interactions with other anticonvulsants and other classes of drugs. § Never withdraw treatment abruptly; if patient is taking several drugs withdraw one at a time. Controlled withdrawal of treatment can be considered after 3-4 years without seizures. § Be very cautious when replacing one drug with another: if possible do not stop first drug before replacement established. § Patients should not drive until they have been free of seizures for at least 1 year. § All antiepileptic drugs should be regarded as potentially teratogenic (esp neural tube defects). Quantitative risk is difficult to assess, but must be weighed against major risk to mother and baby of uncontrolled epilepsy. This is a very important issue. § Phenytoin usage is decreasing with the introduction of the newer drugs. § Anticonvulsants, particularly gabapentin and carbamazepine, are often used in the treatment of neuropathic pain.

Bacteria structure

§ Bacteria are single cell micro-organisms surrounded by a lipid membrane, which in turn is surrounded by a cell wall. They have no true nucleus for the storage of genetic information and do not contain any other membrane-bound organelles. For these reason they are known as 'prokaryotes'. § They constitute an entire phylogenetic domain along with archaea (e.g. Halobacteria, methanogens) and eukaryotes (e.g. protists, fungi, plants & animals) according to the now generally accepted three domain system. 1) Gram positive: These bacteria have a prominent peptidoglycan cell wall, which means that they take up the Gram stain in a simple biological test. A common Gram positive bacterial species is Staphylococcus Aureus. 2) Gram negative: These bacteria have a far less peptidoglycan within their cell wall and prominent levels of peptidoglycan. This means that they do not take up the Gram stain. A common Gram negative bacterial species is Escherichia Coli. 3) Mycolic bacteria: This genus of bacteria does not fit into the classical Gram negative and positive classification; although technical they are considered to be Gram positive, since they do take up the stain but are acid-fast. These bacteria have an outer layer of mycolic acid and a common mycobacterial species is Mycobacterium tuberculosis. This classification is particularly useful for pharmacological purposes since a number of drugs are only effective against one or the other type of bacteria. Drugs that are effective against both Gram positive and Gram negative bacteria are referred to as broad-spectrum antibiotics.

Blood/gas partition coefficient for GA

§ Blood/gas partition coefficient - how a gas will partition itself between the two phases after an equilibrium has been reached: § inhale GA into lungs alveoli. Alveoli are barrier and they will diffuse across as lipid-soluble. § if low BG PC - remained in gaseous state even in blood (doesn't really dissolve) - allows for efficient transfer to brain. can excrete by breathing out (rapid transfer from lungs to brain and back again) § if high BG PC - dissolves well in blood, don't have vast amount available to brain. excreting it out of lungs is muc slower. o 1.38 BG PC = if the gas is in equilibrium, the concentration in the blood will be 1.38x higher in the concentration in the alveoli. o Higher BG PC = slower onset of action as a higher uptake of gas into the blood - takes longer for the brain and blood to reach an equilibrium. **So: § Low BG PC = faster onset of action (drug is more lipophilic and hydrophobic so will not dissolve in blood well). § Inhaled GAs are much easier to control as diffusion occurs very rapidly.

Acetazolamide

§ CARBONIC ANHYDRASE INHIBITORS § Are weak diuretics § Principal site of action = proximal tubule (PCT) § Prevent the reabsorption of HCO3-, Na+; H2O reabsorption is therefore also reduced. § Increase delivery of Na+ to the distal tubule increases K+ loss. § Small increase in tubular fluid osmolarity reduces H2O reabsorption in the collecting duct § Therefore ↑ urine volume and ↑K+, ↑Na+ and ↑HCO3- excretion § Not used as diuretics but are of value in the treatment of glaucoma.

Is alcohol a stimulant or depressant?

§ CNS effects = DEPRESSANT o (Initial stimulatory effects result from depression of inhibitory control pathways) o Impairs - a) Sensory function i.e. Mood Changes e.g. self confidence, euphoria (highly labile at higher concentrations), Memory Loss, Powers of discrimination and concentration. b) Motor function i.e. Slurred speech, Prolonged reaction time, Loss of coordination. § Important - Ethanol has low pharmacological potency i.e. large amounts required to produce effects and little selectivity: Effects generally occur between 40-100mg/100ml §

Cardiovascular effects of COX-2 inhibitors pic

§ COX-2 inhibitors pose a higher risk of CVS disease than conventional NSAIDs - mechanism unclear. o Mechanisms - raise BP, endothelial dysfunction, oxidative injury, etc.

Cannabis immunosuppressant

§ Cannabis acts to depress the immune system by agonising CB2Rs present on the following: o Macrophage. o Mast cell. o B-cell. o T-cell. o Natural Killer cell.

How would cannabis and alcohol act in the brain to influence function (focus your answer on the relevant targets acted on)?

§ Cannabis would bind to CB1 receptors in the brain to induce the relevant effects. CB1 receptors are the most common G-protein coupled receptor in the brain, so cannabis would have widespread effects. § Alcohol is not a selective drug. As a result it induces its effects via an interaction with multiple targets e.g. NMDA receptors, GABA receptors, calcium channels. A large amount of alcohol needs to be administered in order to activate these different targets - alcohol isn't particularly selective for any of them.

After a number of years on sinemet, the patient begins to suffer from dyskinesias and on-off symptoms. 'sinemet' - a combination of levodopa and carbidopa - used to treat Parkinsons Explain why dyskinesias and on-off symptoms might occur. Describe the options for managing these side-effects.

§ Caused by long-term usage of levodopa. The rapid "on-off" effects are possibly due to fluctuations in plasma L-DOPA and a loss in the neurons ability to store DA. The cause of dyskinesias is unknown. § There are limited options for managing these consequences. Use of sustained release preparations of L-DOPA or co-administration of a COMT inhibitor e.g. Entacapone

Pharmacodynamics of cannabis

§ Central effects: o Psychosis, schizophrenia. o Food intake - lateral hypothalamus. o Memory loss - Limbic regions (Amnestic effects/decreased BDNF (Brain Derived Neurotrophic Factor) - key in hippocampus). depressant effect on hippocampus. o Psychomotor performance decreased- affects cerebral cortex. § Peripheral effects: o Immunosuppressant. o Tachycardia/vasodilation - via TRPV1 receptors and NOT CBRs --> leads to red eyes as conjunctiva vasodilate (bloodshot eyes) o the medulla has a LOW CB1R expression and this means that the cardio-respiratory centre is not affected much so it is impossible to overdose on cannabis. ** § Interact with specific endogenous cannabinoid receptors. § Neuronal cannabinoid receptors - CB1; Immune cells - CB2 § Endogenous agonist - anandamide (after Sanskrit word for bliss, ananda); arachidonic acid derivative

innervation of muscles of eye

§ Circular muscles (sphincter pupillae) causes constriction - innervated by PNS fibres of oculomotor nerve. § Radial muscles (dilator pupillae) causes dilation - innervated by SNS fibres. § Lens is under control of the ciliary muscles - innervated by PNS fibres. § Aqueous humour generation: the ciliary epithelium, which consists of 2 layers of ectodermal cells (containing ATPase and carbonic anhydrase), absorbs Na+ selectively from the stroma and transports it to the intracellular clefts, which open on the aqueous humour side.

Which class of anticoagulants to use if clot suspected to form in the future in arterial system?

§ Clot suspected- thrombolytics. § Clot suspected to form in the future in venous system - anticoagulants. § Clot suspected to form in the future in arterial system - antiplatelets

Effects on cannabis on cognition and CVS

§ Cognition and psychomotor performance: Slow reaction times, motor incoordination, defects in short term memory. **Risk factor for severe mental illness!** § CVS effects: a) Tachycardia up to 160 beats/minute b) Widespread vasodilation c) Reddening of the conjunctivae - a characteristic sign of cannabis use d) Postural hypotension and fainting may occur

CD vs UC pathologies

§ Crohn's disease: o Th1-mediated --> worst inflammatory response (florid T cell expansion and lack of apoptosis) o Dependant on TNF-a cytokine. o Penetrates ALL through gut wall (so can get fistulae) o Affects any point of the GI tract. o Causes patchy (not continuous) inflammation. § Hard to cure with surgery and often reoccurs. o Abscesses, fissures and fistula more common. § Ulcerative colitis: o Th2-mediated (limited clonal expansion, and normal apoptosis) o Dependant on IL-5 & IL-13 cytokines. o Affects mucosa and submucosa only (hence unusual to get abscesses, fissures and fistula) o Starts in rectum, spreads proximally. o Always continuous. o Surgery can be curative.

Anti-parkinsonian drugs: summarise and compare the mechanisms of action of drugs used to treat PD. Explain why they are used in conjunction and their limitations

§ DA replacement - Levodopa acts as DA precursor § DA receptor stimulation - D2 agonists: Bromocriptine, ropinirole § Prevention of breakdown - MAOB inhibitors (selegiline), COMT inhibitors (entacapone) § L-DOPA & carbidopa & selegiline - used in conjunction to reduce side-effects & required dosage § Limitations - not disease-modifying § Long-term side-effects associated with levodopa - Dyskinesias & on-off symptoms

Opioids - respiratory depression

§ Depression of the Pre-Botzinger complex in the ventrolateral medulla - this generates respiratory rhythm so less rhythm with depression. § Central chemoreceptors are also inhibited by opioids and so depress the firing rate of the central chemoreceptors. central chemoreceptors respond to co2 levels in blood --> hence urge to breathe is impaired.

Kidney physiology - descending limb cell

§ Descending limb - only H2O reabsorption via AQA molecules. o oncotic pressure and fluid in interstitium is hypertonic and hence water leaves descending limb --> tissue --> blood.

Describe the mechanism of action of diazepam. Benzodiazepines are normally avoided in elderly patients or patients with a history of drug abuse. Why is this so?

§ Diazepam is a positive allosteric modulator of the GABA-A receptor. § Adverse effects include psychomotor impairment, especially in the elderly. This increases the risk of falls and subsequent fracture. § Those with a history of drug abuse - Long term use of benzodiazepines carries an undisputed risk of inducing dependence. Approximately 35% of patients taking benzodiazepines for more than 4 weeks develop dependence as evidenced by the appearance of withdrawal symptoms if dosage is reduced or the drugs are stopped. Factors increasing the risk of dependence include high dosage, regular continuous use, dependent personality characteristics and previous drug dependence. § Also note that benzodiazepiness can potentiate the effects of other CNS depressants.

Design of key statin trials

§ Different trials were designed to measure the effect of statins on different CHD risk groups of patients from low-risk --> high-risk. o 4S1 trial - CHD/high cholesterol group. o WOSCOPS6 - No MI/high cholesterol. § Results showed that irrespective of risk group, all patients benefitted from a 30% reduction in risk. § Lowered LDLs too much resulted in problems in the CNS and memory.

Statin Trials & Spectrum of Risk

§ Different trials were designed to measure the effect of statins on different CHD risk groups of patients from low-risk à high-risk. o 4S1 trial - CHD/high cholesterol group. o WOSCOPS6 - No MI/high cholesterol. § Results showed that irrespective of risk group, all patients benefitted from a 30% reduction in risk. § Lowered LDLs too much resulted in problems in the CNS and memory.

Endogenous pathway of lipid metabolism

§ Endogenous pathway - most LDL/HDL comes from this: o Lipoprotein lipase and Hepatic lipase metabolises the most. o IDL and LDLs are deposited in vessels to form atheromas. *§ Reverse cholesterol transport - the removal of cholesterol from vessel walls back to the liver by HDL.

Exogenous pathway of lipid metabolism

§ Exogenous pathway - when we eat food (TGs and cholesterol), it is broken down into chylomicrons (large) which are further broken down into FFAs and chylomicron remnants. o Chylomicron remnants --> deposit in vessels --> atheroma. *some fat ends up in skeletal muscle and some in adipose tissue. **occurs quickly after fatty meal. *most of cholesterol in circulation is from liver and is endogenous not from food.

Types of general anaesthetics

§ GAs are NOT very structurally similar but they all have similar properties. § The GAs are separated into IV and inhalational types. a) IV generally contain rings e.g. propofol, etomidate b) Inhalational GAs generally have halogens e.g. nitrous oxide, halothane and enflurane.

The rate of Mr Jones' atrial fibrillation had been controlled by a combination of digoxin and a beta-blocker (bisoprolol). At a regular check-up it is found that his ventricular rate has speeded up. One solution might be to increase the dosage of digoxin but, thinking carefully about its mechanism of action, what is the most important blood test that should be checked first and why? How else could you try to ensure that the dose of digoxin is correct?

§ Digoxin binds to the Na/K exchange ATPase on cardiac myocytes. ATPase generates the energy to pump Na+ out of the cell and potassium in. Therefore inhibition of ATPase results an increase in intracellular Na . This reduces the steepness of the sodium concentration gradient across the cell membrane. This in turn sloes down the Na-Ca-exchanger, so less calcium is removed from the cell. The extra Ca is stored in the sarcoplasmic reticulum and is then available for release following an the arrival of an action potential and this results in increased contractility. § Digoxin clearance is almost entirely dependent on renal function especially glomerular filtration rate. It is therefore very important to know if the patient has any renal impairment so that digoxin dose can be adjusted or, if renal function is very poor, the drug can be avoided altogether. It is also essential to know if plasma potassium levels are abnormally low, since hypokalaemia enhances most of the adverse effects of digoxin. Potassium levels should then be corrected (not necessary to discuss here how this should be done). It is possible to measure plasma levels of digoxin directly, since there is a recognised target range for these. It is important to emphasise that toxic effects of the drug, and others, do occur at therapeutic plasma levels. § Digoxin competes with K+ with binding site on ATPase enzyme. If K+ falls, digoxin has a greater effect due to less competition with this binding site. Therapeutic and toxic effects both increased. Commonly prescribed with diuretics which would cause a decrease in plasma K+. Cardiac side effects biggest problem e.g. heart block § Worth noting that the large AFFIRM trial (rate control vs. rhythm control) found that digoxin use was associated with a 42% increase in mortality!

Classification of arrhythmias

§ Disturbance may be brady- or tachy-arrhythmetic in nature. § The simple classification bases the arrhythmia from site of origin: 1) Supraventricular - e.g. amiodarone, verapamil. 2) Ventricular - e.g. flecainide, lidocaine. 3) Complex (supra- and ventricular) - e.g. disopyramide

Diuretics - Common Side Effects (Uric Acid)

§ Diuretic drugs use the OAT to transport into the tubule from the drug and thus can compete with uric acid in the blood. uric acid uses same transporter as diuretics. diuretic has to enter the basal side from blood via OAT, and then goes to lumen where it can act on the apical transporters. uric acid and diuretic compete with diuretic and less excreted. § This can lead to a greater blood concentration of uric acid.

Alzheimer's medication: summarise and compare the mechanisms of action of drugs used to treat Alzheimer's disease

§ Donepezil is a cholinesterase inhibitor with a long duration of action § Rivastigmine also inhibits BChE and is available in patch formulation. § Galantamine has additional nAChR agonist properties § Memantine is a NMDA receptor antagonist licensed for moderate-severe AD

Nicotine dosing

§ Dosing: 1) Nicotine spray - 1mg. 20-50% effective. (intranasal mucous membrane) 2) Nicotine gum - 2-4mg. 50-70% effective. ( mucous membrane in mouth more than oral) 3) Cigarettes - 9-17mg. 20% effective. § pKa = 7.9 - cigarette smoke is acidic so no buccal/mouth absorption. § Absorption in the alveoli is independent of pH however. 4) Nicotine patch - 15-22mg/day. 70% effective.

Alcohol dosing

§ Dosing: o Absolute amount (g alcohol/100ml) = %ABV x 0.78. o Units = (%ABV x volume/ml) / 1000. § 1 unit = 10mls or 8g of absolute alcohol (ethanol) o Low risk - men & women <14units/week. o Binge drinking - >8 units in one sitting.

Drug interactions of TCAs

§ Drug interactions: o PPB (plasma protein bound) - as very PPB, there can be a massive increase of bioavailability if co-administered with something that displaces it from the plasma proteins - e.g. aspirin, phenytoin, warfarin. o Hepatic microsomal enzymes - drugs that compete with the metabolising hepatic enzymes. increased TCA effects as TCAs have slowed metabolism (neuroleptics (anti-psychotics); oral contraceptives). o Potentiation of CNS depressants- drugs that potentiate the effects of the CNS depression - e.g. alcohol. o Antihypertensives - can interact with anti-HT (can make it increase of decrease BP) - (monitor closely)

Phase 2; Glucuronidation

§ Drug-OH + UDPGA --> Drug-O-D-glucuronide. § A high energy phosphate compound is created. §UDP-glucuronic acid is the conjugating agent.

Drug receptor interactions summary slide

§ Drugs can be agonists/stimulatory (e.g. ACh, nicotine) or antagonists/mimic-and-block (e.g. atropine, hexamethonium). o Drugs can also have FULL or PARTIAL agonistic effects. o PARTIAL agonists can lead to some antagonist activity. § 'Potency' of a drug depends upon the: o Affinity - Strength-of-binding/Avidity of the drug to the receptor. o Efficacy - 'intrinsic activity' or biological effect of the drug. § Selectivity - we don't use the word specific as a drug may not be specific to the same receptors at a higher concentration (may bind to other receptors).

Type 2 of drug antagonism: physiological antagonism

§ Drugs that counters the effect of another substance by acting on different receptors. --> opposite effects in same tissue e.g. NA (vasoconstrictor) + histamine (vasodilator) on B.P. If the body has too much NA and thus too much vasoconstriction, histamine can be delivered to counter the vasoconstriction (by acting on H1 receptors instead of adrenergic receptors).

Drugs influencing contractility

§ Drugs: 1) b-blockers - decrease contractility. § Reduces phosphorylation and cross-bridge formation. 2) Calcium antagonists - decrease ICa. § Stops further entry of calcium into myofibrils. § Two classes of calcium antagonists: a) Rate-slowing - cardiac + VSM: § Phenylalkylamines - Verapamil. § Benzothiazepines - Diltiazem. b) Non-rate slowing - VSM (more potent): § Dihydropyridines - Amlodipine. **Note - Non-rate slowing calcium antagonists (Dihydropyridines) have no effect on the heart (just VSM) but the profound vasodilation produced in response can lead to a REFLEX TACHYCARDIA. **All calcium antagonists cause arterial vasodilation and reduce cardiac workload by this mechanism. Verapamil also has negative inotropic and chronotropic actions as a result of reducing Ca2+ entry into cardiac myocytes. Calcium antagonists can cause flushing headaches, hypotension, ankle swelling. Verapamil can also cause heart block, heart failure and constipation.

Drugs influencing heart rate

§ Drugs: a) b-blockers - decrease If and ICa. b) Calcium antagonists - decrease ICa. c) Ivabradine - decrease If. § The drugs reduce the HR by prolonging the extend of the depolarisation: o If or ICa - i.e. decrease the SNS drive. **can use for angina by decreasing HR.

Nausea vs vomiting

§ Nausea - subjective, unpleasant sensation in the throat and stomach; often precedes vomiting. § Vomiting - forceful propulsion of stomach contents out of the mouth. o Both preceded by salivation, sweating and increased heart rate.

Alcohol Chronic effects: Fatty Liver

§ Fatty liver - the lack of NAD+ means that TAGs are deposited in the liver. (after night out, but reversible if stop drinking for 24 hours). § Hepatitis - mixed function oxidases are upregulated in chronic alcoholics and these generate free radicals which then generate an inflammatory response. o MFO --> free radicals --> inflammation. o Cytokines are then released - e.g. increased IL-6 and TNF-a.(STILL REVERSIBLE, but if enough fibroblasts can lead to...) § Cirrhosis - fibroblasts lay down fibrin supportive structures that reduce regenerative capacity of liver - decreased regeneration and active liver tissue. Increased fibroblasts. Downstream, toxic levels build up in blood and need liver transplant.

Alcohol Chronic effects: Hepatitis

§ Fatty liver - the lack of NAD+ means that TAGs are deposited in the liver.(after night out, but reversible if stop drinking for 24 hours). § Hepatitis - mixed function oxidases are upregulated in chronic alcoholics and these generate free radicals which then generate an inflammatory response. o MFO --> free radicals --> inflammation. o Cytokines are then released - e.g. increased IL-6 and TNF-a. (STILL REVERSIBLE, but if enough fibroblasts can lead to...) § Cirrhosis - fibroblasts lay down fibrin supportive structures that reduce regenerative capacity of liver - decreased regeneration and active liver tissue. Increased fibroblasts. Downstream, toxic levels build up in blood and need liver transplant.

Alcohol Chronic effects: cirrhosis

§ Fatty liver - the lack of NAD+ means that TAGs are deposited in the liver.(after night out, but reversible if stop drinking for 24 hours). § Hepatitis - mixed function oxidases are upregulated in chronic alcoholics and these generate free radicals which then generate an inflammatory response. o MFO --> free radicals --> inflammation. o Cytokines are then released - e.g. increased IL-6 and TNF-a.(STILL REVERSIBLE, but if enough fibroblasts can lead to...) § Cirrhosis - fibroblasts lay down fibrin supportive structures that reduce regenerative capacity of liver - decreased regeneration and active liver tissue. Increased fibroblasts. Downstream, toxic levels build up in blood and need liver transplant.

Why is a reversible anti-cholinesterase (e.g. physostigmine) cleared from the body more rapidly than an irreversible anti-cholinesterase (e.g. sarin gas)?

§ Firstly, imagine two body compartments i.e. plasma and tissue (could be any tissue). Now think in terms of simple diffusion in relation to concentration gradients. When drugs initially enter the bloodstream, the plasma concentration is obviously high. As blood passes through the various tissues, the drug diffuses from the plasma (high concentration) to the tissue (low concentration). [Caveat - the better perfused the tissue, the faster this happens] At some point an equilibrium would be reached, and there would be no net transfer from plasma to tissue and vice versa. However, drug metabolism acts to constantly shift this equilibrium. As the drug is metabolised, the plasma drug (morphine/ibuprofen) concentration reduces, and the concentration gradient shifts so that drug diffuses from tissue to plasma. Over time, as the plasma drug concentration reaches zero, the drug will be completely lost from the tissues as it diffuses back across into the plasma. § In this case, because physostigmine is reversible, as the drug is cleared from the body, so the equilibrium shifts and the drug exits the tissue and enters the plasma, where it will subsequently be metabolised e.g. in the liver. Eventually, the physostigmine will be completely cleared from the body. In the case of sarin gas, an irreversible bond is formed with the cholinesterase. As a result, the sarin gas is not free to diffuse back out of the tissue into the plasma even though the concentration gradient is shifting. In this case, the tissue would need to degrade/internalise the sarin gas bound cholinesterase and replace it with new cholinesterase. This is a much slower process than drug clearance and as a result the effects of the sarin gas would persist for far longer than the physostigmine.

complicated plaque formation in atherosclerosis

§ Formation of fibrous cap (collagen) § Accumulation of macrophages. § Formation of necrotic core (Smooth muscle cells and macrophages). •This results from the death and rupture of the foam cells in the fatty streak. •You get formation of a necrotic core. •The migration of smooth muscle cells into the intima and laying down collagen fibres results in the formation of a protective fibrous capover the lipid core. •The fibrous cap is extremely important because it separates the highly thrombogenic lipid-‐rich core from circulating platelets and coagulation factors. •Stable atherosclerotic plaques are characterised by a necrotic lipid core covered by a thick vascular smooth muscle-‐rich fibrous plaque.

Dosing of cocaine

§ Forms of cocaine - gets purer/stronger as you go down: o Oral, IV, intranasal; cannot heat it as it breaks down: 1) "Paste" or cocaine sulphate - 80% cocaine (organic solvent). 2) "Cocaine HCl" - dissolved in acidic solution. o Inhalational: 1) "Crack" - precipitated with alkaline solution (e.g. baking soda). smokable form of cocaine. 2) "Freebase" - dissolved in a non-polar solvent (e.g. ammonia + ether. purer form

Gaba-ergic synapse

§ GABA synthesised from precursor glutamate in TCA cycle. 1. Glutamate --> GABA via GAD (Glutamate Decarboxylase) - take off one carboxyl group. GABA stored in vesicles. When AP arrives, GABA exocytosis into cleft. 2. GABA can bind to: a. GABAAR on the postsynaptic cell --> hyperpolarise cell. Leads to chloride influx. b. GABABR on pre-synaptic cell --> -ve inhibition of release. 3. GABA can then be re-up-taken by: a. Glial cells - GABA-Transaminase breaks down GABA into SSA (Sunninic Semialdehyde). b. Pre-synaptic cell - GABA-T breaks down GABA into SSA. *there are gaba autoreceptors that sit on presynaptic terminal (like a2 receptors for adrenergic) - regulate release of GABA. if too much GABA, it decreases GABA release. GABA-b does same thing. **generally GABA neurones in brain are the short axon interneurones. sit in discrete brain areas e.g. hippocampus to damp down hyperactivity. *nigrostriatal pathway uses alot of dopamine, degeneration of this tract (substantia nigra to corpus striatum) --> Parkinsons. the descending tract from striatum to substantia nigra is a gaba-ergic pathway.

Gaba Metabolism

§ GABA via GABA-T --> Succinic Semialdehyde (SSA) via SSDH --> Succinic Acid (goes back into TCA cycle (GABA shunt)). § GAD is found in the cytosol whilst GABA-T and SSDH are found in the mitochondrial membrane. § Inhibitors of GABA metabolism lead to more GABA and more inhibition in the brain. This is used in some drugs: o E.G. a) Sodium Valproate (epilim) - weak GABA-T inhibitor but also inhibits SSDH enzyme. Also binds to and blocks VGSCs (voltage gated sodium channels). b) Vigabatrin (sabril) - GABA-T inhibitor (suicide inhibitor as binds tightly so increases GABA conc.). first rationally designed drug for epilepsy treatment.

Glucocorticoids MOA and unwanted effects

§ Glucocorticoids (GCs) are ANTI-inflammatory drugs that activate intracellular GC receptors. The activated receptors then act as positive transcription factors, increasing the expression of antiinflammatory genes or, more frequently, negative transcription factors, reducing the expression of pro-inflammatory genes. § They act on many cell types and have powerful anti-inflammatory actions including a reduction in the influx and activation of proinflammatory cells and a reduced production of the mediators which cause vasodilation, fluid exudation (swelling), further inflammatory cell recruitment and tissue degradation. § Additionally, GCs are potent IMMUNOSUPPRESSIVE drugs, causing reductions in antigen presentation, cell proliferation and clonal expansion. **SIDE EFFECTS: § Because of structural similarities between synthetic GCs and the endogenous hormone, CORTISOL, GCs tend to have many unwanted side effects. The incidence and severity of side effects are closely related to the dose and duration of GC given. § Unwanted effects of GCs are (Cushings symptoms): o Osteoporosis o Increased risk of Gastric ulceration o Suppression of HPA axis o Type II diabetes o Hypertension o Susceptibility to infection o Skin thinning, bruising and slow wound healing o Muscle wasting and buffalo hump § GCs play a key role in the management of CD, so strategies have been developed for minimising their unwanted effects. § These strategies include the use of TAPERED doses, the use of drugs with a HIGH therapeutic index such as fluticasone, and TOPICAL administration (particularly of budesonide which has a high first pass metabolism in the liver and GIT). § Because of their unwanted effects, GCs are best used to treat ACTIVE disease rather than to maintain remission and prevent relapse. § Despite their powerful anti-inflammatory actions, they are less effective than aminosalicylates in the treatment of UC.

HIV entry inhibitors

§ HIV is a lentiviral retrovirus responsible for causing acquired immunodeficiency syndrome (AIDS). It is relatively large for a virus and contains two copies of single stranded RNA enclosed within an icosahedral capsid. This in turn is surrounded by a phospholipid envelope containing numerous transmembrane glycoprotein complexes. HIV has the ability to infect a variety of immune cells including CD4+ T-lymphocytes, monocytes and macrophages. By compromising the activity of these cells and the immune response, HIV leaves the infected individual highly susceptible to variety of opportunistic infections. 1.Attachment & Entry: § HIV Glycoprotein (GP)120 attaches to CD4 receptor § GP120 also binds to either CCR5 or CXCR4 co-receptors. § GP41 penetrates host cell membrane & viral capsid enters 1) Enfuvirtide: •Binds to HIV GP41 transmembrane glycoprotein. Don't use that much anymore as is a S/C injection twice a day. 2) Maraviroc: •Blocks CCR5 chemokine co-receptor. **people with delta-32 mutation, don't encode CCR5 and hence do not get HIV. **2 people in world have been cured from HIV, they have leukaemia --> got chemo and then got a bone marrow transplant from donor with delta-32 mutation.

MOA of statins

§ HMG-CoA Reductase inhibitors. o This halts the cholesterol synthesis pathway. o Halts specifically the rate-limiting step. o Reduces the modification of proteins involved in modifying gene translation to create LDL. § This has the effect of UP-REGULATING the LDL receptors expressed on hepatocytes in the liver which results in more LDL being removed from the blood. § This also results in more HDL levels in the blood

Tenofovir vs ribavirin

§ Hepatitis B & C - only chronic infection requires treatment. 1) Hepatitis B treatment: a) Tenofovir - nucleoTide analogue. · Reverse transcriptase inhibitor. · Given occasionally with Peginterferon alfa. 2) Hepatitis C treatment: a) Ribavirin - nucleoSide analogue. · Purine analogue. · Given with Peginterferon alfa. b) Boceprevir - protease inhibitor. · Most effective against HepC genotype 1.

Inhalation Vs. Intravenous entry to body

§ IV is more straightforward into blood; Inhalation goes through lungs. § IV agents: o The time the IV agent is active is dependent on the liver metabolism. o The IV agents are injected directly into the blood where they pass to the brain. § Inhalational agents: o Inhaled agents pass from the air to the blood and to the brain so have an extra membrane to diffuse through.

GAs - Clinical Setting for loss of consciousness and reflex suppression

§ IV is used for induction. § Inhalation is used for maintenance.

Why is true incidence of Drug-Drug Interactions difficult to determine?

§ Incidence is difficult to ascertain due to: o Data for drug-related hospital admissions do not differentiate out drug interactions, only ADRs. o There is a lack of available comprehensive databases. o Difficulty in assessing OTC drug use. o Difficulty in determining drug contribution to interactions in complicated patients. o Sometimes the principal causes of ADRs is with specific drugs - e.g. statins.

Ezetimibe

§ Inhibits cholesterol absorption. § absorbed ezetimibe --> glucuronide (in the intestines) - ACTIVATED. § on own decreases cholesterol by 15%. Can be co-administered with statins to avoid the "rule of 6" with statins to have a more dramatic effect at lowering LDL. if double, get more than 6% reduction. but is still a modest effect.

LDL cholesterol

§ LDL - strongly associated with atherosclerosis & CHD events. o - 10% increase LDL --> 20% increase in CHD events. o These events are modified by - smoking, low HDL, hypertension & diabetes o cholesterol is a modifiable risk factor: 10% reduction in total cholesterol --> 15% reduction in CHD mortality and 11% reduction in total mortality. **§ HDL - protective effect for atherosclerosis & CHD events. o HDL tends to be low when TG are high. o HDL is lowered by - smoking, obesity, physical inactivity.

Frusemide

§ LOOP DIURETICS § Powerful diuretics § Locus of action ascending limb of loop of Henle (see below) - Inhibit the triple transporter (Na, Cl, K) **Consequences: o Failure to reabsorb Na+ and Cl- dilutes the medullary interstitium and therefore reduces the concentrating power of the collecting duct o Ca2+ and Mg2+ reabsorption is also impaired o Increased delivery of Na+ to the late distal tubule activates the Na+/K+ exchange mechanism o Large volume of urine, increased excretion of Na+, K+, Cl-, Ca2+ and Mg2+ o Possible metabolic alkalosis **Clinical uses: o Acute pulmonary oedema, o edema due to heart failure, liver disease or renal disease (if refractory to other diuretics, o Hypercalcaemia, o Hyperkalaemia, o Acute renal failure (may facilitate urine flow).

Cocaine: Pharmacodynamics - Local anaesthetic

§ Local anaesthetic - high-dose cocaine: o Cocaine (+ve charged) can block the sodium channels to cause a local anaesthetic effect - blocks sodium influx and inhibits conduction of AP. o much better if cocaine enters channel from inside the cell (7.4pH outside nerve; pH is 7 inside; hence outside cell it is more unionised --> diffuse across plasma membrane --> more charged/ionised and can access inside of channel and is better at interacting with channel).

GAs - Mechanism of action: Neuroanatomy - loss of consciousness

§ Loss of consciousness: a) Depress thalamocortical neurones. § GAs hyperpolarise thalamocortical neurones by activating TREK channels and/or by potentiating GABA Rs. b) Influence RAF neurones. The GAs will disrupt the communication between the RAF, cortex and thalamus. **The reticular activating system (RAS) emanates from the brainstem and projects upward to the cerebral cortex via the thalamus. All the cortical varieties of consciousness depend upon the integrity of these subcortical structures. Acetylcholine is released from cholinergic nerve terminals projecting from RAS to the thalamus and cortex in highest concentrations in association with cortical activation that occurs naturally during wakefulness. Consciousness depends on feedback loops between cortex, thalamus and reticular activating system. Sensory information received by the cortex is the primary starting point for consciousness. Anaesthetics can directly hyperpolarize thalamocortical neurons by activating TREK channels and/or by potentiating GABAAreceptors - information transfer through the thalamus is disrupted. Although the thalamus might control the state of consciousness, processing in the cortex is responsible for the detailed content of consciousness, and during anaesthetic-induced LOC the cortex is profoundly deactivated.

GABAA-Receptor Mechanisms of activation

§ Mechanisms of activation: 1) Pathway 1 - linkage of GABA-RP, GABA-M and BDZ-RP and opening of Cl—channel. *GABA*. 2) Pathway 2 - initiation of pathway 1. *BDZ*. 3) Pathway 3 - increased affinity of binding of GABA/BDZ (reversible). *GABA, BDZ*. 4) Pathway 4 - linkage of Barb-RP and BDZ-RP and opening of Cl—channel. *Barb*. 5) Pathway 5 - increased affinity of binding of GABA (NOT-reversible). *Barb*. 6) Pathway 6 - direct activation of Cl—channel. *GABA, Barb*

Kidney Physiology - (Early) Distal Convoluted Tubule:

§ Mediated by the Na+/Cl—co-transporter. o Draws more ions into the interstitium. § Impermeable to free water reabsorption, mediated mainly by selective AQA2 channels under VP control (much more common in late DCT than early though). § No gap junctions so not permeable to free re-uptake. hence need aquaporins o another mechanism for water entry, sodium and chloride entry. o still has Na/KATPase to maintain

Metabolism of BDZs

§ Metabolism o Metabolism of BDZs seen on the left. o Diazepam is long-acting (32h half life). o Temazepam (8h) and Oxazepam (8h) are short-acting. o The final excreted products are glucuronide conjugates (via kidney)

Metabolism of cocaine

§ Metabolism: o 75-90% is metabolised very fast into: § Ecogonine methyl ester. § Benzoylecgonine. (these metabolites are INACTIVE) o T1/2 = 20-90 minutes. o Plasma and liver cholinesterase's. hence can be metabolised in blood.

Metabolism of nicotine

§ Metabolism: o Nicotine T1/2 = 1-4 hours. o Hepatic CYP-2A6 metabolises 70-80% --> cotinine. o Cotinine is not active and rapidly cleared. **LIKE cocaine is addictive - because fast onset and metabolised rapidly to inactive metabolite (cotinine). cocaine is metabolised faster as metabolised in blood.

Routes of administration for drugs of abuse

§ Methods of administration: o Intranasal - slow absorption. § Mucous membranes of nasal sinus before bloodstream. o Oral - very slow absorption in GIT, then liver then blood, then heart, then lung, then heart, then brain.. o Inhalational - rapid absorption. small airways and alveoli. o Intravenous - rapid absorption. **Fastest route to the brain is inhalation as pulmonary circuit is very short (already in pulmonary circulation, don't need to go back to heart to lungs to get oxygenated to then get pumped to brain; can get straight pumped to brain) o whereas IV must do the systematic circuit before accessing the brain. **Ascending order on onset of euphoria - Oral < Intranasal < IV < inhalational.

fatty streak formation in atherosclerosis

§ Migration of VSMCs. § Activation of T-cells. § Adherence & activation of platelets. § Formation of foam cells. •The fatty streak is the earliest recognisable lesion of atherosclerosis and is caused by the aggregation of lipid-‐rich foam cells(derived from macrophages and T lymphocytes within the tunica intima) . •Later on the lesions will also include smooth muscle cells. •The fatty streaks are usually formed in the direction of blood flow

Fibrates

§ MoA - PPAR-alpha receptor agonist present in nucelus. o PPAR - Peroxisome Proliferator Activated Receptors. o Act on the liver. § Decrease FFAs and TGs. § Increases HDL very effectively but LDL doesn't change a lot (most effective on patients with low HDL and not super high levels of LDL). o overall decrease TGs and FAs. § NOTE: Thiazolidinediones - PPAR-gamma receptor agonists. o They are different! o Act on adipose tissue.

Monoamine theory of depression

§ Monoamine theory of depression - depression is a functional DEFICIT of central MA transmission; Mania is a functional EXCESS of MA transmission. o This is mirrored by NA and 5-HT (serotonin) deficits/excesses (depression= depletion in the levels of serotonin, NA) § There is good pharmacological evidence to support this theory but biological evidence is inconsistent. reserpine used to be used as anti-HT drug until depressive effects seen (prevents loading of NA and 5-HT into vesicles) § cocaine may seem to be argument against it because it decreases NA but no anti-depressant effect. o Biological evidence: § A reduction in NA metabolites is not concurrent with a worse depression. § Delayed onset of the clinical effect of drugs (a few weeks sometimes) - possibly due to adaptive changes in brain and not MA theory causing depression: o There is a downregulation of - a2, b and 5-HT receptors. **General conclusions still remain firm for MA theory of depression. § Some recent studies say depression could also be due to HPA axis and increased CRH (and thus cortisol) or hippocampal neurodegeneration.

Mycobacteria

§ Mycobacteria are classified as Gram positive bacteria but have an outer wall that is significantly more complex than other Gram positive bacteria. The outer wall contains a PtG-arabinogalactan polymer that binds mycolic acids, pore forming proteins and a number of extractable lipids giving the bacteria a 'waxy' outer layer. § The most notable examples of mycobacteria are responsible for tuberculosis (mycobacteria tuberculosis) and leprosy (mycobacteria leprae). **Tuberculosis treatment: The RNA-polymerase inhibitor rifampicin is one of the first-line drugs recommended for the treatment of tuberculosis but two of the other drugs are specific for mycobacteria and are classified as mycolic acid synthesis inhibitors. Although isoniazid and ethambutol have slightly different modes of action their eventual effect is to prevent the synthesis of mycolic acid. The fourth drug used in the treatment of tuberculosis is pyrazinamide, which is thought to reduce the availability of ribosomes required for protein translation. Previous Page

MoA of most neuroleptics

§ Neuroleptic drug actions: o D2-receptor antagonists - ALL neuroleptics. o Block other receptors - e.g. 5-HT - MOST neuroleptics. § Drugs tend to treat the positive symptoms of the disease but not the negative ones! § Because neuroleptics are D2 antagonists correcting the over activity of dopamine in the mesolimbic system and striatum but have no effect on the forebrain dopamine deficits where the negative symptoms are produced. § Neuroleptics have a delayed effect, take weeks to work. This may be due to the fact that initially neuroleptics induce an increase in dopamine synthesis and neuronal activity, and an increase indopamine receptors on the target cells. However this declines with time.

Nicotine - Pharmacodynamics nAChR

§ Nicotine binds to nicotinic receptors and stimulates Na+ transport. o drives sympathetic and parasympathetic function o involved in ANS.

Nicotine, cannabis and cocaine may all be taken to attempt to improve mood. Explain the mechanism of action of each of these drugs in relation to their ability to elevate mood.

§ Nicotine binds to nicotinic receptors on the cell body of the cell body of the dopaminergic neurones originating in the ventral tegmental area. This directly stimulates this neurone and increases dopamine release increasing feeling of reward/improving mood. § Cannabis binds to cannabinoid receptors on GABA interneurones. The depressant effect on the GABA neurones leads to less inhibition of the dopaminergic neurones originating from the VTA. As a result, more dopamine is released increasing feeling of reward/improving mood. § Cocaine blocks dopamine reuptake in the nucleus accumbens. This increases the life of dopamine in the synaptic cleft and leads to increased feelings of reward. **Extra info - you might be interested in the link between cannabis and schizophrenia. Can cannabis induce psychosis/schizophrenia or do schizophrenic patients take cannabis to alleviate symptoms? No easy answer, although high potency cannabis has been associated with an increase in psychotic symptoms. One current hypothesis is that newer high potency forms of cannabis (e.g. skunk) have increased levels of delta-9-THC (associated with increased psychotic symptoms) at the expense of decreased levels of cannabidiol (believed to reduce risk of psychosis).

How do opioids induce euphoria?

§ Opiates bind to the Mu receptor and decrease GABA exocytosis (disinhibition) § This reduces the inhibition on the VTA so more DA is released from NAcc)

What are the three types of opiate receptors and their endogenous ligands

§ Opioids act via specific "opioid" receptors. § Opioid peptides include - Endorphins, Enkephalins and Dynorphins/Neoendorphins. § The table to the left shows the receptors they act on: o Endorphins --> Mu/Delta receptors --> pain/mood/CVS/sensorimotor o Enkephalins --> Delta --> pain/mood/CVS. o Dynorphins --> Kappa --> appetite. *PAG = Periaqueductal Grey Matter.

What do family studies say about phenotype differences arising from?

§ Phenotype differences arise from genotype differences and there may be more than one genotype. § There may be one or more genotype encoding the proteins required for metabolism and these again may be dominant or recessive. This can give rise to phenotypically different people (polymorphisms): § For example, one allele (F) confers FAST enzyme activity and another enzyme (S) confers slow enzyme activity: o F x F Homozygous FAST metaboliser. o F x S Heterozygous metaboliser. o S x F Heterozygous metaboliser. o S x S Homozygous SLOW metaboliser. § Dominant or recessive: o If neither trait is dominant or recessive, then ALL THREE genotypes will appear in a population as THREE PHENOTYPES in a tri-modal distribution. o If the fast or slow is dominant, then the heterozygotes will appear as phenotypically fast/slow metabolisers and so there will be a bi-modal distribution with 2 overall phenotypes. o This can be investigated with "Family units" or "Pedigree studies" which investigate whether a trait is inherited with simple mendelian inheritance. § The key lies in determining the PHENOTYPE of the HETEROZYGOTE GENOTYPE. § In practice, other genetic influences can blur the distinction.

Summarise the physiological control of nausea/vomiting and identify the main mechanistic triggers

§ Physiological control: Chemoreceptor Trigger Zone (CTZ): receives multiple inputs from areas including stomach & vestibular nuclei CTZ: communicates with the vomiting centre à nausea & vomiting § Mechanistic triggers: Cytotoxic drugs, motion sickness, gastrointestinal problems, pregnancy, other higher functions

Which receptors does cannabis act on?

§ Receptors (cannabinoid receptors): 1) Brain - CB1R - Hippocampus, cerebellum, cortex and basal ganglia. the most common GPCR in brain. 2) Peripheral - CB2R - Immune cells. *is a depressant: § The CBR is an inhibitory GPCR linked to AC (decrease cAMP and cell activity). § Endogenous Anandamide (comes from cholesterol and lipid membranes etc.) and is the body's version of THC that binds to these receptors.

HIV Replication inhibitors

§ Reverse transcription: •Viral single-stranded RNA --> double stranded DNA by reverse transcriptase a) Nucleoside RT inhibitors: •Activated by 3 step phosphorylation process. Is pro-drug. blocks formation of DNA. •E.g. Zidovudine b) Nucleotide RT inhibitors: •Fewer phosphorylation steps required •E.g. Tenofovir c) Non-nucleoside RT inhibitors: •No phosphorylation required •Not incorporated into viral DNA. Has many CNS side-effects tho: insomnia, depression etc. •E.g. Efavirenz.

Rhythym disturbances

§ Rhythm disturbances are relatively common - 70,000 in the UK. § Aims of treatment: a) reduce sudden death b) alleviate symptoms c) prevent stroke. § Management is complex for rhythm disturbances and often includes non-drug approaches. Usually undertaken by specialists and may involve cardioversion, pacemakers, catheter ablation therapy and implantable defibrillators as well as drug therapy. § Disturbance may be brady- or tachy-arrhythmetic in nature. § The simple classification bases the arrhythmia from site of origin: 1) Supraventricular - e.g. amiodarone, verapamil. 2) Ventricular - e.g. flecainide, lidocaine. 3) Complex (supra- and ventricular) - e.g. disopyramide

Effects of statins on lipids

§ Rosuvastatin has the greatest effect in reducing LDL and raising HDL, however, just a modest effect in reducing TG. § "Rule of 6" - doubling the dose ONLY makes a 6% extra reduction.

Anti-TNFa in IBD (infliximab)

ØUsed successfully in the treatment of CD not UC; but potentially now seeing some increased efficacy (potentially implying it could be bit Th1-mediated like crohn's) Ø Only 60% patients respond within 6 weeks Ø Potentially curative, but many patients relapse Ø Successful in some patients with refractory disease and fistulae Ø Very good for maintaining fistula closure

Aspirin is selective for which enzyme?

§ Selective for COX-1. § Binds IRREVERSIBLY to COX enzymes (odd for NSAIDs) --> more long lasting and can only be reversed by de novo synthesis of new enzyme. § Actions - anti-inflammatory, analgesic, anti-pyretic. § Reduces platelet aggregation: 1) Platelets: § Reduces TXA2 production via COX1, no re-production as the platelet has no nucleus. 2) Endothelial cells: § Reduces PGI2 (prostacyclin) synthesis by COX1/2. Reproduction possible due to nucleus and so can replenish prostacyclin. thus prostacyclin reduced but not complete blockade. get higher ratio of prostacyclin to thromboxane. o Thus, less TXA2 and still PGI2 so reduced platelet aggregation. ***Side effects of aspirin: o Gastric irritation, ulceration, bleeding and, in extreme cases, perforation. o Reduced creatinine clearance and possible nephritis. o Prolonged bleeding times, due to reduced platelet aggregation. o Bronchoconstriction in susceptible individuals.

Mechanism of effect of nicotinic acid

§ Should be very good but turns out in clinical practice it isn't so not used very much. o high S/E and toxicity.

Are bacteria multicellular? What proportion are pathogenic? What are the different classes?

§ Single-cell microorganisms - cell wall & cell membrane § An entire phylogenetic domain § ~ 1/3 are pathogenic **Membrane properties: 1) Gram Positive Bacteria: •Prominent peptidoglycan cell wall with cell membrane underneath. Take in gram stain (purple) •E.g. Staphylococcus Aureus 2) Gram Negative Bacteria: •Outer membrane with lipopolysaccharide. smaller peptidoglycan cell wall underneath. Inner membrane is similar to that of gram positive bacteria. Don't take gram stain (pink) •E.g. Escherichia Coli 3) Mycolic Bacteria: •Outer mycolic acid layer. Outside reasonably prominent peptidoglycan cell wall . Don't either take in or not take in gram stain. •E.g. Mycobacterium Tuberculosis

How does cannabis cause euphoria through CB1 receptor?

§ Stimulation of the GI CB1 (inhibitory GPCR) receptor inhibits the release of GABA. o leads to DISINHIBITION (gaba is switched off; disinhibit dopaminergic projection neurones)... § This increases the release of dopamine by inhibiting the inhibition of release of DA in NAcc

Phase 2; Sulphation

§ Sulphotranferases catalyse transfer of sulphate to substrates. §3'-phosphoadenosine-5'-phosphosulphate is the conjugating agent.

Hangover

§ Symptoms peak as BAC approaches 0. o Nausea: acetaldehyde irritant --> vagus --> vomiting centre of medulla. o Headache: Vasodilation due to acetaldehyde o Fatigue: Sleep deprivation, 'rebound' and also diuresis due to decreased VP. o Restlessness and muscle tremors: 'rebound' - rebound excitation as BAC --> 0. o Polyuria, polydipsia: Decreased VP secretion. **CURE?? o Sleep o Water drinking - does it help clear toxins (e.g. acetaldehyde?) o 15min water load is largely excreted AND Water mixed with an easily absorbed sugar is largely excreted (hence squash might be better).

Bendroflumethiazide (bendrofluazide)

§ THIAZIDE § Moderately powerful diuretic § Locus of action: early distal tubule - inhibition of Na+ and Cl- reabsorption in the early distal tubule. **Consequences: § Increased delivery of solute to the collecting duct reduces water reabsorption - urine volume is thus increased § Mg2+ reabsorption is also impaired but Ca2+ reabsorption is increased § Increased delivery of Na+ to the late distal tubule activates the Na+/K+ exchange mechanism § Increased excretion of Na+, K+, Cl-, and Mg2+but reduced loss of Ca2+. **Clinical uses: § Congestive heart failure § Hypertension § Idiopathic hypercalcaemia § Nephrogenic diabetes insipidus

Beta blocker targets for treating hypertension

§ Targets: o CNS - to reduce sympathetic tone. o Heart (b1) - reduce ionotropic and chronotropic effect (this effect disappears in chronic treatment). o Kidneys (b1) - reduce renin production (common long term feature is a reduction in TPR). § Also note the b1-receptor on the pre-synaptic membrane and thus blockade of this reduces positive feedback on NE release and may contribute to anti-hypertensive effects.

Where in pain transmission pathway could opioids act?

§ The Mu receptors impact the analgesic effect the most. § Main targets of opioids: 1) Dorsal horn and periphery - increase inhibition (suppress transmission of pain) 2) PAG - enhance firing (by suppressing GABA, and disinhibiting PAG) 3) NRPG - activates. § Opioids are very good at switching OFF GABA. o GABA has an inhibitory effect on many of the pain tolerance centres so blocking GABA activates the pain tolerance centres.

When should we use COX-2 inhibitors?

§ The NICE guidelines recommend that selective COX-2 inhibitors should only be used in patients at high risk of GI side effects, i.e.: a) Those with a history of ulcers/GI bleeding b) Patients over 65 c) Patients taking other drugs which increase risk of GI side effects d) Patients needing maximal doses of NSAIDS long-term. § The reason that COX-2 inhibitors are not recommended for use in all patients is that, whilst their use diminishes gastrointestinal risk, they increase the risk of cardiovascular events. § The reasons for this are currently poorly understood, but a contributory factor may be that they selectively inhibit PGI2 production whilst sparing the production of TxA2.

What is the most potent cannabinoid?

§ The cannabis is the plant, the hashish/resin is the trichomes (glandular hairs that contain the highest concentration of THC) and the hash oil is the solvent extract. § Cannabis contains over 400 compounds with >60 being cannabinoids. o Delta9-THC (Delta9-Tetrahydrocannabinol) is the most potent cannabinoid. o Positive aspects of smoking weed are from cannabidiol - experts believe a balance between these two (cannabidiol vs. delta9-THC) is needed.

Amyloid hypothesis for AD (1/3)

§ beta amyloid plaques thought to be involved in AD. § amyloid is Physiologically processed in body by two enzymes: 1.Amyloid precursor protein (APP) cleaved by a-secretase 2.sAPPa released - C83 fragment remains 3.C83 --> digested by g-secretase 4.Products removed. (so first cleaved by alpha --> then gamma secretase --> then product removed). **Pathophysiological processing: 1.APP cleaved by B-secretase 2. sAPPb released - C99 fragment remains (longer product) 3.C99 --> digested by g-secretase releasing b-amyloid (Ab) protein 4.Ab is the major constituent of amyloid plaques, which forms toxic aggregates and clumps inside and mostly outside neurone outside membrane. can also clump on other CNS cells. Thought this results in immune reaction --> destruction of neurones. Or alternatively, the plaques themselves cause damage to neurones. (so first cleaved by beta --> then gamma secretase --> then beta amyloid aggregates). **Thought that tau aggregation occurs, then beta amyloid aggregation. So both can occur together.

Several months later it is noticed in the anticoagulant clinic that the INR has fallen sharply and that he therefore needs a much higher dose of warfarin. He tells the doctor in the clinic that he has felt depressed, so he has been taking St John's wort which he buys from a health food shop. What is INR, how is it measured and what does a fall in INR signify? Why might his self-medication with St John's wort be relevant to the change in warfarin requirement? What else might do this?

§ The prothrombin time, or PT, test measures the time it takes for a blood sample to clot, but the results of the prothrombin time test may vary from lab to lab, because of differences between different batches and manufacturers. Therefore the International Normalised Ratio (INR) is used to standardise the results. § Each manufacturer gives an ISI (International Sensitivity Index) for any tissue factor they make. The ISI value indicates how the particular batch of tissue factor compares to an internationally standardized sample. The ISI is usually between 1.0 and 1.4. §The INR is the ratio of a patient's prothrombin time to a normal (control) sample, raised to the power of the ISI value for the control sample used. § The normal range for INR is 0.9-1.2. When the INR falls below 2.0 thrombosis risk increases and when the INR rises above 4.0 serious bleeding risk increases. The recommended INR for patients with a history of atrial fibrillation is 2.0 - 3.0. § Sr John's wort, widely used as a self-administered antidepressant, contains a compound (called hypericin) which is an inducer of the cytochrome system and therefore speeds up the clearance of warfarin. There are fewer enzyme inducers than inhibitors, or at least we think so because there are probably many in plants still to be recognized. Other drugs that have similar effects include: o rifampicin, used in TB therapy - short half life, therefore induction within 24h. o carbamazepine and phenytoin, as well as the older and largely obsolete antiepileptic drugs phenobarbitone and primidone - t1/2 3-5days therefore induction after 1 week. o the antifungal drug griseofulvin § Hypericin has weak monoamine oxidase activity. Another component of St John's wort - hyperforin is believed to inhibit serotonin reuptake and therefore convey most of the anti-depressant activity.

Opiate structure-activity: morphine

§ The tertiary form nitrogen appears to be crucial to the ANALGESIC effect. Making nitrogen quaternary appears to decrease the analgesic effect greatly (since it cannot pass into the CNS). o The tertiary nitrogen permits receptor anchoring (important in affinity) o Extending the side chain (3+ C) --> change from agonist to antagonists. § Changes to the methyl group will also decrease the analgesic effect - This is how you create antagonists. § hydroxyl groups - sites of modification

Cannabis in health and disease

§ There is upregulation of CBRs in: o MS/pain/stroke patients - to regulate pain (protective effect) o Fertility/obesity - this is pathologic and may contribute to obesity (found in adipose tissue) and infertility (esp. in males, decrease testosterone, inhibit pituitary gland in driving gonadal function, interfere with sperm production) § DRUGS: o Autoprotection - Dronabinol, Nabilone, Sativex: § Dronabinol, Nabilone - Anti-emetics in cancer; stimulate appetite. § Sativex - analgesic; treat MS pain. o Autoimpairment - Rimonabant. § Rimonabant - Anti-obesity drug (off-market). · Blocks the feeling of hunger. depression and suicide associated, hence off market now.

What effect would diuretics have on renin secretion? Which diuretic would have the most powerful effect on renin secretion?

§ This is a macula densa cell that detects the tubular concentration of Na+ in the late ascending thick limb of the LoH. § What effect would diuretics have on renin secretion? o Decreased sodium load in the tubule will increase renin secretion to promote sodium reabsorption therefore diuretics would promote renin secretion (due to decreased sodium and renal perfusion pressure from water loss). § What diuretic would have the greatest effect on renin secretion? o Loop diuretics would have the greatest effect as they retain more sodium in the tubule. because the protein the triple transporter that transports sodium into the macula densa cell is same transporter blocked by loop diuretics. Hence activation of RAAAS is counter-productive. § These effects result in resistance to chronic use of diuretic. hence give ACEi alongside diuretics to stop RAAS activation.

Muscarinic receptor antagonists examples

§ This is mainly a PNS antagonist as the only muscarinic receptor in the SNS is found in sweat glands. o So expect mainly inhibition of PNS. § Two examples of MRAs are: o Atropine. o Hyoscine.

Yellow card scheme

§ This was a scheme introduced after the 1964 incident with thalidomide and is run by the Committee on Safety of Medicines (branch of medicines control agency - MHRA). § Voluntary, can be used by any healthcare professional and member of public, and includes blood products, vaccines and contrast media. § Established drugs --> only report serious adverse reactions. § "Black triangle" drugs (newly licensed, usually <2 years) --> report ANY suspected adverse reactions.

Alcohol - tolerance and dependence

§ Tolerance to effects of ethanol occurs rapidly (1-3 WEEKS with continuing ethanol administration) § Due to: o Pharmacokinetic tolerance o Tissue tolerance o Cellular adaptation § Dependence = Overpowering craving for alcohol § Physical withdrawal characterized by; Tremor, hallucinations, convulsions, behaviour disturbances, nausea, fever

Hypertension treatment

§ Treatment overview: 1) Step 1 - Single Therapy: § Under 55 - ACEi OR ARB (Angiotensin Receptor Blocker). § Over 55, Afro-Caribbean - CCB or Thiazide diuretic. 2) Step 2 - Dual Therapy: § ACEi and CCB. § ACEi and thiazide diuretic. § ARBs preferred to ACEi for AfroCaribbean's 3) Step 3 - Triple Therapy: § ACEi, CCB and thiazide diuretic combination. 4) Step 4 - Symptomatic Relief (resistant hypertension): § Low-dose spironolactone (diuretic therapy). § b-blockade or a-blockade.

What are the two classes of calcium antagonists?

§ Two classes of calcium antagonists: a) Rate-slowing - cardiac + VSM: § Phenylalkylamines - Verapamil. § Benzothiazepines - Diltiazem. b) Non-rate slowing - VSM (more potent): § Dihydropyridines - Amlodipine. **Note - Non-rate slowing calcium antagonists (Dihydropyridines) have no effect on the heart (just VSM) but the profound vasodilation produced in response can lead to a REFLEX TACHYCARDIA.

The figures show the effects of Drugs A & B compared to placebo on a) CNS beta-amyloid levels & b) Alzheimer's disease symptoms in a patient suffering from mild/moderate disease. Asterisks denote a significant difference compared to placebo. Analyse the effects of drugs A & B compared to placebo

§ drug A significantly decreased CNS-beta amyloid levels. could be solanezumab. § drug B significantly improved AD symptoms. could be donepezil.

Structure-activity relationship in drug-receptor interaction

Þ 'lock and key' (key is drug and lock is receptor) Þ agonists --> antagonists Þ pharmacokinetics

Some months later Mr Jones again complains of anxiety and poor sleep at night. His GP prescribes a benzodiazepine, temazepam. The day after he has taken the first dose his wife rings the surgery to say he has been very confused overnight. She notes that this has never happened with her 45 year old daughter who takes the same pill. What might be the reason for this difference?

§ Two main reasons. The metabolism by the liver of some drugs, but not all, is reduced in older patients. Some drugs which are very similar can behave very differently: this is often unpredictable. In addition older patients may have increased sensitivity to drugs even in metabolism is normal. The basis of this is very poorly understood, and it is not known whether this is related to receptor number or function, or some other mechanism(s). § Temazepam is metabolized directly by phase II metabolism that seems relatively unaffected by aging. Temazepam less lipophilic than other BZPs, therefore levels in blood likely to be relatively higher (since older people generally have more body fat). § Digoxin has been suggested to have anti-cholinergic effects in older patients, particularly if patient is on multiple medications. Confusion might be one of the CNS outcomes of the anti-cholinergic effects.

What are the two major forms of IBD?

§ Two major forms of IBD - the distinction is incomplete in ~10% of patients (Intermediate Colitis): 1) Ulcerative colitis. 2) Crohn's disease - most studied of the two. § Affects ~300,000 people in the UK. **IBD double in western > eastern europe --> shows lifestyle affects. **genetic risk factors: o Causes incompletely understood o CD more extensively studied than UC oGenetic predisposition: •201 loci identified •People of White European origin most susceptible **Both are immune disorders which are believed to be triggered by an abnormal response to bacterial lipopolysaccharide. **Although the clinical distinction between UC and CD is not always absolutely clearcut, they tend to have a number of distinctive features including their responsiveness to drug therapies. § Treatment falls into two parts, the treatment of active disease and the maintenance of remission in order to prevent relapse. § When medical treatments fail, surgery may be necessary. § Surgery is curative in UC, but not always in patients with CD in whom the inflammation may subsequently flare up in a different region of the gastrointestinal tract.

Hyoscine is used to treat what kind of N&V? unwanted effects?

§ USE AS AN ANTI-EMETIC: Prevention of motion sickness. o Has little effects once nausea/emesis is established. o In operative pre-medication. o NOTE: Atropine is less effective. § UNWANTED EFFECTS: Typical anti-muscarinic side-effects: drowsiness, dry mouth, cycloplegia, mydriasis, constipation (not usually at anti-emetic doses). § PHARMACOKINETIC CONSIDERATIONS Can be administered orally (peak effect in 1-2 hours), i.v., transdermally.

When is ondansetron used?

§ USE AS AN ANTI-EMETIC: o main use in preventing anticancer drug-induced vomiting, especially cisplatin. o radiotherapy-induced sickness. o post-operative nausea and vomiting. § UNWANTED EFFECTS: headache, sensation of flushing and warmth, increased large bowel transit time (constipation). § PHARMACOKINETIC CONSIDERATIONS: Administer orally; well absorbed, excreted in urine

Unwanted effects of BDZs (-epam, -epate)

§ Unwanted effects of BDZs: a) Sedation, confusion, amnesia, ataxia - all impaired manual skills. b) Potentiates other CNS depressants. c) Tolerance (less than barbs and includes "tissues only") and dependence: Withdrawal syndrome (less intense than barbs). Hence we withdraw BDZs slowly (over couple weeks). d) Free plasma concentration increases when co-administered with aspirin, heparin: Displace the BDZ from binding plasma proteins hence increases BDZs action.

Alcohol acute effects: CVS vasodilation

§ Vasodilation: o Cutaneous vasodilation - flushing. § Decreased Ca2+ influx --> less VSM contraction (prevents precapillary sphincters from keeping contracted --> blood flow) - think it's due to acetaldehyde. § Increased prostaglandins (vasodilators).

Opioids - Dependence

§ Withdrawal associated with: o Psychological craving. o Physical withdrawal (resembling the flu): § Opioids normally depress cell activity by reducing AC activity and cAMP and so when opioid not there the body responds by upregulating AC activity. When you remove the opioid drug, the body is overstimulating AC and so general cell activity is greatly increased for a few weeks after --> withdrawal. This causes increased muscular contractions and cramps.

A man suffers an anaphylactic reaction after being stung by a wasp. The paramedic injects the man with adrenaline in an attempt to preserve the airways (induce bronchodilation) and increase blood pressure (oppose hypotension). § What effect would you expect the injected adrenaline to have on sweat production?

§ You need to ensure you understand that agonists tend to bind with relative selectivity for specific receptors. You might be confused by the fact that sweating is a sympathetically mediated process, but in this particular case the sympathetic nerve would release acetylcholine. Acetylcholine binds to acetylcholine receptors (in this case, muscarinic receptors) and therefore sweating is induced by acetylcholine release from sympathetic nerves acting on muscarinic receptors. In the case of adrenaline, the receptors of importance are the adrenergic receptors - which do not directly mediate sweating.

Benzodiazepines pharmacokinetics

§ around 20 available: All act on GABAA receptors (not GABAB), have similar potencies and profiles but it's the pharmacokinetics that differentiate use: o The durations of action vary greatly. § Pharmacokinetics: 1) Administration: - orally or IV (IV only used for status epilepticus), peak plasma at ~1h. 2) Distribution: Binds plasma proteins strongly, high lipid solubility --> wide distribution 3) Extensive liver metabolism. 4) Excretion - urine (glucuronide conjugates). 5) Duration of action - VARIES GREATLY: a) Short-acting BZs b) Long-acting BZs- slow metabolism and/or generate active metabolites.

Clinical uses of salbutamol

§ b2>>b1>>>a1/a2. § Synthetic catecholamine derivative with resistance to COMT and MAO. § Clinical uses: a) Treatment of asthma. § b2 relaxation of smooth muscle. § Inhibition of release of bronchoconstriction substances. b) Treatment of threatened pre-mature labour. § b2 relaxation of smooth muscle. § Side effects - reflex tachycardia, tremor, blood sugar dysregulation

Unwanted effects of azathioprine

ØNearly 10% patients have to stop treatment because of side effects ØPancreatitis ØBone marrow suppression ØHepatotoxicity ØIncreased risk (~ 4 fold) of lymphoma and skin cancer

Structure of the virus

§ genetic material (RNA or DNA) § capsid (protein shell surrounding the genetic material of virus) § lipid envelope § envelope proteins o A virus particle (a virion) consists of a small segment of genetic material (DNA or RNA) surrounded by a protein capsule, known as a capsid. o Since they do not have a defined cellular structure or their own metabolism they are unable to reproduce without a host cell and are therefore known as obligate parasites. o The viral genetic material contains the information that is required to create its own microenvironment and also program the synthetic machinery of the host cell for viral replication. o The capsid serves to protect the genetic material from dangers such as nucleases in the external environment. It can also play an important role in attachment of the virion to the host membrane, which would ordinarily repel the negatively charged DNA or RNA. The capsid and the viral genome along with any associated nucleoproteins are referred to as the nucleocapsid. o A number of viruses also have a protein coat, which is a lipid bilayer quite often derived from the membrane of the host cell. The bilayer generally contains a number of integral membrane proteins and glycoproteins that are coded for by the viral genome. These integral membrane proteins often play an important role in the entry and exit of viruses into host cells.

GA MoA theory 1: Lipid theory of GAs

§ more lipid soluble a GA become --> more potent. Anaesthetic potency increases in direct proportion with oil/water partition coefficient (Meyer/Overton Correlation) Meyer-Overton correlation - GAs penetrate the lipid bilayer and disrupt AP propagation: a. Evidence for - anaesthetic potency increases as lipid solubility increases. b. Evidence against - at relevant concentrations, changes in the bilayer was minute and no changes in lipid bilayer proteins was seen (which would be changed if GAs disrupted AP propagation). Also did not see how the GAs could interfere with membrane proteins (e.g. channel proteins) to change bilayer permeability.

What are the two classes of drugs used for AD?

§ orange receptor is NAchr in CNS - activated by Ach (green molecule). 1)Anticholinesterases: a) Donepezil § Reversible cholinesterase inhibitor (acetyl and glutyryl cholinesterase) § Long plasma half-life (only needs to be administered once daily) § first-line treatment. b) Rivastigmine: § Pseudo-reversible AChE & BChE inhibitor (BChE inhibitor not necessarily good thing --> lots of S/E) § 8 hour half-life § Reformulated as transdermal patch (so more selective within CNS). c) Galantamine § Reversible cholinesterase inhibitor § 7-8 hour half-life § a7 nAChR agonist **these drugs have beneficial effect - increases amount of Ach available and reverses some of symptoms seen in AD e.g. improves memory. but this effect only lasts for about 2 years. they treat symptoms but not the actual underlying physiology. These drugs are used for mild-moderate AD. BUT Donepezil can be used for mild, moderate and severe. **Note: subunits expression differentiates between AchR in muscle (3a, b and y) and in neuronal (5a subunits). 2) NMDA receptor blocker: a. Memantine: § Use-dependent non-competitive NMDA receptor blocker with low channel affinity (only be effective if having excessive NMDA activity - i.e. in severe neurodegeneration - as alot of gaba disappeared so get lots of Glu activation). § ONLY licensed for moderate-severe AD § Long plasma half-life

Mannitol

§ osmotic diuretic § Pharmacologically inert § Filtered by the glomerulus but NOT reabsorbed § Increase the osmolarity of tubular fluid (NB + plasma) § Acts where H2O reabsorption where the nephron is freely permeable to water: proximal tubule, descending, loop of Henle & collecting duct

GABAA receptor complex

§ post-synaptic § The GABAA-R is made up of 4 main proteins: o GABA-R Protein. o GABA modulin. o Barbiturate receptor protein. o BDZ (Benzodiazepine) receptor protein. § has chloride channel protein in middle. § Bicuculline (GABA) and Flumazenil (BDZ) are competitive antagonists: a) bicuculline - competes with GABA competivetly to bind to GABA receptor protein. b) flumazenil - BDZ competitive antagonist by binding to BDZ receptor protein. used to reverse ODing of BDZs. § BDZ and Barb require GABA to some degree to function. § when GABA binds get linking of GABA receptor protein and BDZ receptor protein via GABA modulin --> opening of chloride channel --> chloride influx --> hyperpolarisation of post-synaptic cell. § BDZ enhances chloride influx and enhances binding of GABA to GABA receptor protein (reciprocal response - so when GABA binds, BDZ binds better as well to BDZ receptor protein). § barbiturates also bind to own barbiturate receptor protein: they enhance normal action of GABA by increasing chloride channel opening (indirectly and directly) and enhances binding of GABA to GABA receptor protein BUT this is not reciprocal like with BDZ.

Dopamine synthesis and metabolism

§ red circle in pre-synaptic dopaminergic neurone is vesicle. **Synthesis: o L-tyrosine--> (i) --> L-DOPA --> (ii) --> Dopamine (DA) o This process utilises the enzymes: i.Tyrosine hydroxylase (rate-limiting step) ii.DOPA decarboxylase. § dopamine stored in vesicle till released. **Metabolism: o Once DA had it's effect, DA removed from synaptic cleft by dopamine transporter (DAT) & noradrenaline transporter (NET) - present on pre-synaptic neurone and DAT also on glial cell. o Three enzymes metabolise DA: 1)Monoamine oxidase A (MAO-A): metabolises DA, NE & 5-HT 2)MAO-B: metabolises DA 3)Catechol-O-methyl transferase (COMT): wide distribution (glial cell and post-synaptic), metabolises all catecholamines.

Mechanisms by which statins reduce elevated LDL

§ statins are HMG-CoA Reductase inhibitors. o This halts the cholesterol synthesis pathway. o Halts specifically the rate-limiting step. o Reduces the modification of proteins involved in modifying gene translation to create LDL. § This has the effect of UP-REGULATING the LDL receptors expressed on hepatocytes in the liver which results in more LDL being removed from the blood. § This also results in more HDL levels in the blood

How azathioprine can cause side effects?

ØNearly 10% patients have to stop treatment because of side effects ØPancreatitis ØBone marrow suppression ØHepatotoxicity ØIncreased risk (~ 4 fold) of lymphoma and skin cancer. § Three main routes of metabolism of 6MP: 1) HPRT - beneficial but causes myelosuppression. 2) TPMT - hepatotoxic metabolites. 3) XO - inert metabolites - IDEAL and main pathway. § However, a drug called allopurinol (treats gout) inhibits CO and so blocks this pathway. Overall: *6-TGN --> myelosuppression *6-MeMP --> hepatotoxic *6-MP --> allipurinol (drug given for gout) inhibits xanthine oxidase. inhibiting this reduces conversion of 6-MP to 6-TU (inactive metabolite) --> 6-MP goes more to other routes and can get blood disorders.

Describe the actions of other antiviral drugs

ØNucleoside analogues - Ribavirin, Aciclovir ØProtease inhibitors - Boceprevir ØNeuraminidase inhibitors - Oseltamivir

How many different modes did you observe in this population?

§ two modes. § the first mode runs from O.D. values 0 to 0.5. This contains patients who have relatively less blue coloration in their urine and hence smaller amounts of N-acetylated metabolites. They are relatively bad or SLOW metabolisers. contains 99/195 patients = 51% § the seond mode runs from O.D. values 0.61 to 1.00. This contains patients who have relatively more blue coloration in their urine and hence larger amounts of N-acetylated metabolites. They are relatively good or FAST metabolisers. contains 97/196 patients = 49%. § there is an antimode at O.D. values 0.51 to 0.60. no patients occupy this position. **this tells us phenotype, we want genotype. Hence we look at family. Everyone is fast metaboliser but the eldest daughter. This say that slow acetylation is the recessive; parents are heterozygous. Slow phenotype is composed of one genotype (homozygous slow): SS. The fast phenotype is composed of two genotypes (homozygous fast and heterozygous): FF, FS/SF. *using the hardy-weinberg quadratic equation and info gathered from the population study, calculate the frequency of three genotypes. (FF, FS, SS): o the proportion of the population who reside within the slow phenotype mode and are thus the slow genotype (SS, q squared) = 51%. o as q squared = 51%, if we square root --> 0.71 = q. o p + q=1. o hence, p = 1 - 0.71 = 0.29. o genotype frequencies are therefore: § FF (p squared) = (0.29 x 0.29) = 0.0837 = 8.37% (around 16 patients) § SS (q squared) = (0.71 x 0.71) = 0.5051 = 50.51% (around 99 patients). § FS (2pq) = 2 x 0.29 x 0.71 = 0.4112 = 41.12% (around 81 patients).

Schizophrenia: identify the principle neurotransmitter defects in schizophrenia

§Increased DA in mesolimbic pathway: Positive symptoms --> hallucinations § Reduced DA in mesocortical pathway: Negative symptoms --> affective flattening

Parkinson's Disease treatment (2+3/3)

§Receptor activation: o Dopamine (DA) can act on D1,5(Gs linked) or D2-4 (Gi-linked) receptors. o DA is re-uptaken by the dopamine transporter (DAT) & metabolised by monoamine oxidase (MAO) enzymes o advantage as not relying on a pre-synaptic neurone as part of mechanism. 1)Dopamine receptor agonists: a) Ergot derivatives (derived from naturally occurring substances): Bromocriptine & Pergolide - o Act as potent agonists of D2 receptors o BUT Associated with fibrosis of cardiac valves. b) Non-ergot derivatives (more synthetic - used more than ergot derivates): Ropinirole & Rotigotine - o Ropinirole also available as extended-release formulation o Rotigotine also available as a patch 2)Monoamine oxidase B (MAOB) inhibitors: Selegiline (deprenyl) & Rasagiline - o Reduce the dosage of L-DOPA required o Can increase the amount of time before levodopa treatment is required o limited by 'cheese reaction'

Alzheimer's disease: identify the underlying pathology, the clinical symptoms and risk factors

§b- amyloid plaques due to incorrect processing of APP §Tau hyperphophorylation leading to the formation of neurofibrillary tangles §Inappropriate activation of microglia §Main risk factor - Age §Memory loss, disorientation/ confusion, language problems, personality changes, poor judgement

Directly Acting SNS Agonists

·Adrenaline - non-selective ·Phenylephrine - Alpha 1 ·Clonidine - Alpha 2 ·Isoprenaline - Beta selective ·Dobutamine - Beta 1 ·Salbutamol - Beta 2 **Selectivity depends on CONCENTRATION ·At low concentrations these drugs will be relatively selective but if you increase its concentration, the chance of binding to other receptors increases

Azathioprine in IBD

Ø A pro-drug Activated by gut flora to 6-mercaptopurine Ø so can give 6-mercaptopurine directly Ø Purine antagonist (thus interferes with DNA synthesis and cell replication) Ø Hence, immunosuppressive. § Azathioprine is used mainly to maintain remission in CD. § It is a pro-drug which is activated by the gut flora to its active component 6-mercaptopurine, which, as its name indicates, is a purine analogue which works by interfering with purine biosynthesis and hence with DNA synthesis. § It impairs cell- and antibody-mediated immune responses, mononuclear cell infiltration, lymphocyte proliferation and the synthesis of antibodies, whilst enhancing T cell apoptosis. § Because it is metabolised by the enzyme xanthine oxidase, it should not be administered with allopurinol, a drug used for the treatment of gout, which works by inhibiting this enzyme.

Clinical features of IBD

ØAbdominal pain and crampitng ØDiarrhoea, bloody faeces ØMouth ulcers ØAnaemia ØFever ØArthritic pain ØSkin rashes ØUveitis ØWeight loss **systemic signs are seen esp. in Crohn's.

How many people affected by Schizophrenia?

ØAffects ~ 1% of population & has strong genetic influence - identical twins have a 50% chance of being both affected if one has it. ØOnset of symptoms: between 15-35 years ØHigher incidence in ethnic minorities (eg Afro-Caribbean immigrants) ØPatients' life expectancy - 20-30 years lower than average because of lifestyle choices made by them - due to high drug users, smokers and suicide levels. **Aetiology - Unknown, but several hypotheses including, may be due to a slow viral infection possibly linked with an auto-immune process. Alternately, may be due to a developmental abnormality ~ anatomical changes in the temporal lobes (entorhinal cortex, hippocampus) and amygdala - Mesolimbic system.

Opioids - Overdose

ØComa ØRespiratory depression ØPin-point pupils ØHypotension (due to histamine release). Ø Treatment:Naloxone (opioid antagonist) i.v: o Naloxone also has a tertiary nitrogen and so can bind to the opioid receptors. o Naloxone has a LONG side chain of carbons and so has ANTAGONISTIC properties once bound to the opioid receptors (extended side chain)

When to use infliximb?

ØEarly use better than last resort ØCombined infliximab and azathioprine therapy recommended rather than monotherapy Ø not something that can be used long-term

Summarise the mechanisms of action of antiretroviral drugs

ØEntry inhibitors - Enfuvirtide & Maraviroc ØRT inhibitors - Nucleoside analogues (Zidovudine), Non-nucleoside analogues (Efavirenz) ØIntegrase inhibitors - Raltegravir ØProtease inhibitors - Saquinavir

Distinguish between different types of virus and describe how they use the host cell to replicate

ØHIV - Retrovirus, leukocytes ØHepatitis - DNA & RNA viruses, hepatocytes ØHerpes Simplex - DNA virus ØInfluenza - RNA virus

Classification of drugs of abuse

ØNarcotics/Painkillers - opiate like drugs e.g. heroin ØDepressants - 'downers' e.g. alcohol, benzodiazepines (valium), barbiturates ØStimulants - 'uppers' e.g. cocaine, amphetamine ('speed'), caffeine, metamphetamine ('crystal meth') ØMiscellaneous - e.g. Cannabis, Ecstasy (MDMA). o These drugs have effects from multiple classes. **Ascending order on onset of euphoria - Oral < Intranasal < IV < inhalational.

What are the most common phase 2 metabolic reactions for paracetamol

• Paracetamol is a widely used analgesic and antipyretic drug. • It is taken orally, absorbed and distributed throughout the body enabling pain and fever relief. • It is largely metabolised in the liver which results in excretion of paracetamol as non-toxic metabolites. • It can cause liver damage after over-dosage. § Phase 1 metabolism of paracetamol is mediated by Cytochrome P450 enzymes and results in the formation of a reactive intermediate, NAPQI. § Common phase 2 reactions include; methylation, acetylation, sulphation, glucuronidation, amino acid conjugation and glutathione conjugation. § Paracetamol often undergoes: o Glucuronidations - 60-80% - enzyme; UDP-glucuronosyltransferase, substrate; UDP-glucuronic acid (UDP-GA). o Sulphonations - 20-40% - enzyme; sulphotransferase, substrate; PAPS (3'phosphoadenosyl-5'-phosphosulphate). § NAPQI is electrophilic and so is further metabolised and detoxified by another phase 2 reaction; glutathione conjugation (often detoxifies) - glutathione attacks the electrophilic carbon on the carbon ring. § In a case of acute poisoning and knowing the molecular products of metabolism of paracetamol, it is possible to salvage the toxicity of the case by giving oral/IV N-acetylcysteine or methionine (s-adenosyl-methionine). o This gives the body the ability to create more glutathione so it can metabolise the paracetamol faster. § Distribution of paracetamol metabolites in different compartments of the body; o Serum - parent drug (paracetamol). o Urine - small amount of parent drug, sulphated paracetamol. o Bile - glucuronidated paracetamol, glutathione - metabolites too large to be passed in urine. § The plasma half-life of paracetamol in patients with liver damage due to overdose is over twice that than in normal human subjects after a therapeutic dose. This is due to liver damage meaning less glucuronidation can occur as the pathway is saturated (sulphates depleted so this pathway is closed). Also the paracetamol can be metabolised to NADQI and then possibly back again into paracetamol by a backward pathway which increases the half-life. § Acetanilide is a pro-drug of paracetamol and caused methaemoglobinaemia and as a result was removed from the market and replaced with paracetamol. Acetanilide is oxidised to form paracetamol. It's when acetanilide is hydrolysed that it causes methaemoglobinaemia.

Definition of epilepsy

•A neurological condition causing frequent seizures •Seizures are "sudden changes in behaviour caused by electrical hypersynchronization of neuronal networks in the cerebral cortex" § the diagnosis of epilepsy implies that the seizures are UNPROVOKED. In most practical situations, epilepsy is said to be present when two ore more attacks have occurred -this is an epidemiological definition that reflects the fact that patients with two or more attacks are likely to go to have further attacks without anticonvulsant medication.

Treatment of Organophosphate Poisoning

•Accidental exposure to organophosphates used in insecticides, or deliberate use as nerve agents can cause severe toxicity ( muscarinic activity; CNS excitation; depolarising NM block) •Treatment: IV atropine; artificial respiration; IV pralidoxime - reverse cholinesterase block but has to be done within couple hours so Ach can be broken down •NB: Phosphorylated enzyme 'ages' within few hours - just keep them alive until then

Directly acting SNS agonist examples

•Adrenaline (non-selective) •Phenylephrine (a1) •Clonidine (a2) •Dobutamine (b1) •Salbutamol (b2)

.Identify the drugs used in the treatment of peptic ulcers and their mechanisms of action

•Antibiotics: removal of H pylori infection •Proton pump inhibitors: e.g. omeprazole - reduce acid production from parietal cells •Histamine H2 antagonists: reduce acid production from parietal cells

Physiology and pathophysiology of hypertension

•Blood pressure (BP) = cardiac output (CO) x total peripheral resistance (TPR) (from BVs and renin) * Pathophysiology: •Hypertension is defined as being consistently above 140/90 mmHg •Single most important risk factor for stroke, causing about 50% of ischaemic strokes •Accounts for ~25% of heart failure (HF) cases, this increases to ~70% in the elderly •Major risk factor for myocardial infarction (MI) & chronic kidney disease (KD) •Ultimate goal of hypertension therapy ---> reduce mortality from cardiovascular or renal events

Two main iso-forms of COX

•COX-1 and COX-2 with different (but overlapping) cellular distributions •Aspirin is COX-1 selective and particularly bad at causes ulcers •Maybe COX-2 selective NSAIDS won't cause ulcers •Coxib family: selectively reversibly inhibit COX-2 (example: celecoxib) o it works are stopping ulcers!! BUT... •Evidence that selective COX-2 inhibitors pose higher risk of cardiovascular disease than conventional NSAIDS even though mechanism is unclear **MEDLEARN: § COX-1 is constitutive (i.e. it is present all the time). It is found in many cell types and its main roles are in the regulation of homeostatic functions (make sure you can name some examples). § In contrast, COX-2 is mainly inducible and by cell types than COX1 and in particular by pro-inflammatory cells such as leukocytes. It has both pathological and physiological functions. § Both COX isoforms catalyse two different reactions. The first step is an oxygenation, which converts arachidonate to PGG2. The second step is a peroxidation, catalysed by a different part of the enzyme, which converts PGG2 to the product PGH2.

Name 6 phase 2 reactions

•Conjugate is almost always pharmacologically inactive •More Polar •Easier to excrete. * Glucuronidation is quantitatively most important *Glutathione is a protective factor, used for the removal of potentially toxic compounds (reacts with electrophiles) (Glycine + glutamine + cysteine tripeptide)

Treatment for DVT

•DALTEPARIN then RIVAROXABAN / WARFARIN

Muscarinic effects: summary

•Decreased heart rate •Decreased blood pressure •Increased sweating •Difficulty breathing •Bladder contraction •Gastrointestinal pain •Increased salivation and tears

Muscarinic effects on CVS

•Decreased heart rate (bradycardia) •Decreased cardiac output (due to decreased atrial contraction) •Vasodilatation (stimulation of NO production) •All of these combined can lead to a sharp DROP in BP (hypotensive)

Muscarinic agonist 1/2: pilocarpine

•Derived from the leaves of a South American shrub Pilocarpus •Non-selective muscarinic agonist (doesn't choose between M1, M2 and M3 but is selective between nicotinic and muscarinic ); good lipid solubility; t1/2 ≈ 3-4h •Particularly useful in ophthalmology as a local treatment for glaucoma e.g. eyedrops • Side effects: Blurred vision (due to bulging of lens), sweating, gastro-intestinal disturbance and pain, hypotension, respiratory distress

What is first pass metabolism?

•First pass metabolism is the metabolism of the drug in the body before it reaches the systemic circulation

Butyrylcholinesterase is found where? selectivity?

•Found in plasma and most tissues (e.g. liver, skin) but NOT cholinergic synapses •BROAD substrate specificity - hydrolyses other esters e.g. suxamethonium •Is principal reason for low plasma acetylcholine •Shows genetic variation

Major side-effects of Aspirin seen at therapeutic doses

•Gastric irritation and ulceration •Bronchospasm in sensitive asthmatics •Prolonged bleeding times •Nephrotoxicity •Side effects likely with aspirin than other NSAIDS because it inhibits COX covalently and irreversibly, not because it is selective for COX-1.

Explain the underlying pathology of peptic ulcers

•Helicobacter pylori: increases gastric acid formation; decreases gastric metaplasia; increases defence factors •Proton pump: H+ secretion - activated by increased Ca2+ and increased cAMP •Histamine released from ECL cells act on H3 receptors- increased cAMP

HSV-1 and HSV-2 tropisms

•Herpes Simplex Virus (HSV)-1 --> cold-sores •HSV-2 --> genital herpes § There are more than 100 known members of the herpesvirus family but only 8 of these are known to infect humans. § There are two serotypes of the herpes simplex virus, known as herpes simplex virus-1 (HSV-1) and herpes simplex virus-2 (HSV2). § HSV-1 is generally associated with infections around the mouth and lips (i.e. cold sores) whereas HSV-2 more commonly affects the genitalia (i.e. Herpes). § Varicella zoster is responsible for causing chicken pox upon primary infection. Chicken pox is a highly contagious acute illness generally affecting young children, resulting in itchy lesions (pox)on the skin. § Once the illness has resolved the virus is not eliminated and lies latently within the nerve cell bodies. The virus can subsequently become reactivated many years later causing shingles. § The antiviral compounds recommended for the treatment of HSV and varicella zoster include the nucleoside analogue aciclovir.

Muscarinic effects on exocrine glands

•Increased salivation •Increased bronchial secretions •Increased gastro-intestinal secretions (including gastric HCl production) •Increased sweating (SNS-mediated)

Effects of cholinesterase inhibitors: high dose (toxic)

•Low dose -Enhanced muscarinic activity (see above) •Moderate dose -Further enhancement of muscarinic activity -Increased transmission at ALL autonomic ganglia (nAChRs) - as start to stimulate nicotinic receptors •High dose (toxic) -Depolarising block at autonomic ganglia & NMJ - can give rise to respiratory depression

Effects of cholinesterase inhibitors: low dose

•Low dose -Enhanced muscarinic activity (see above) •Moderate dose -Further enhancement of muscarinic activity -Increased transmission at ALL autonomic ganglia (nAChRs) - as start to stimulate nicotinic receptors •High dose (toxic) -Depolarising block at autonomic ganglia & NMJ - can give rise to respiratory depression

Effects of cholinesterase inhibitors: moderate dose

•Low dose -Enhanced muscarinic activity (see above) •Moderate dose -Further enhancement of muscarinic activity -Increased transmission at ALL autonomic ganglia (nAChRs) - as start to stimulate nicotinic receptors •High dose (toxic) -Depolarising block at autonomic ganglia & NMJ - can give rise to respiratory depression

Effects of cholinesterase inhibitors

•Low dose -Enhanced muscarinic activity (see above) •Moderate dose -Further enhancement of muscarinic activity -Increased transmission at ALL autonomic ganglia (nAChRs) - as start to stimulate nicotinic receptors •High dose (toxic) -Depolarising block at autonomic ganglia & NMJ - can give rise to respiratory depression **§ Alzheimer's Disease: o Donepezil and Tacrine are used to treat Alzheimer's disease (which proves ACh is important in learning and memory). o Potentiation of central cholinergic transmission relieves AD symptoms but does not affect degeneration.

Cholinesterase enzymes do what? What are the two types?

•Metabolise acetylcholine to choline and acetate •Two types which differ in distribution, substrate specificity and function: 1) Acetylcholinesterase (true or specific cholinesterase) 2) Butyrylcholinesterase (pseudocholinesterase)

Muscarinic agonist 2/2: bethanechol

•Minor modification of acetylcholine, produces an M3 AChR selective agonist •Resistant to degradation (e.g. by cholinesterases), orally active and with limited access to the brain (t1/2 ≈ 3-4h) •Mainly used to assist bladder emptying and to enhance gastric motility •Side effects: sweating, impaired vision, bradycardia, hypotension, respiratory difficulty •[Cevimeline - newer M3-selective cholinomimetic]

Muscarinic vs nicotinic effects

•Muscarinic effects are those that can be replicated by muscarine, and can be abolished by low doses of the antagonist atropine. •Muscarinic actions correspond to those of parasympathetic stimulation •After atropine blockade of muscarinic actions, larger doses of acetylcholine can induce effects similar to those caused by nicotine

Examples of muscarinic receptor antagonists

•Nicotinic receptor antagonists (ganglion blocking drugs) -Hexamethonium (1st Hypotensive) -Trimetaphan (Hypotension during surgery, short acting) -Alpha-bungarotoxin - irreversibly binds to both somatic and autonomic nicotinic receptors • Muscarinic receptor antagonists -Atropine (given for organophosphate poisoning) -Hyoscine -Tropicamide •Botulinum toxin - targets snare complex, preventing exocytosis of ACh

Anticholinesterase Drugs & the CNS effect with different doses

•Non-polar anticholinesterases (e.g. physostigmine; nerve agents) can cross the blood brain barrier •Low doses: Excitation with possibility of convulsions •High doses: Unconsciousness, respiratory depression, death

Irreversible Anticholinesterase Drugs

•Organophosphate compounds: ecothiopate, dyflos, parathion and sarin •Rapidly react with the enzyme active site, leaving a large blocking group - This is stable and resistant to hydrolysis - recovery may require the production of new enzymes (days/weeks) - Only ecothiopate in clinical use, but the others are commonly used as insecticides (and as nerve gas!)

COX-1 and COX-2 enzymes in the nephron

•PGE2 increases renal blood flow •NSAIDs can cause renal toxicity: a) Constriction of afferent renal arteriole b) Reduction in renal artery flow c) Reduced glomerular filtration rate **COX1 and 2 are distributed between, hence COX1 and 2 are interlinked so tricky even when selectively inhibiting just one isoform.

Unwanted Effects of adrenaline

•Secretions: reduced and thickened mucous, which leads to a dry mouth •CNS: minimal, (doesn't cross the BBB very well) •CVS effects: Tachycardia, palpitations, arrhythmias, cold extremities (due to peripheral vasoconstriction), severe hypertension. Overdose may cause cerebral haemorrhage and pulmonary oedema from extreme hypertension •GI tract: minimal •Skeletal muscle: stimulation of the β-receptors may cause a tremor

Muscarinic effects on non-vascular smooth muscle

•Smooth muscle that does have parasympathetic innervation responds in the OPPOSITE way to vascular muscle - i.e. it CONTRACTS. •Lung: Bronchoconstriction •Gut: Increased peristalsis (motility) •Bladder: Increased bladder emptying - more conventional excitatory responses

CYP 450 Inhibitors examples

•The "usual suspects" -Cimetidine (H2 antagonist for stomach acid) -Erythromycin and related antibiotics -Ketoconazole etc -Ciprofloxacin and related antibiotics -Ritonavir and other HIV drugs -Fluoxetine and other SSRIs -Grapefruit juice **Inhibition is very rapid (mins/hours) §Inducers: -Rifampicin -Carbamazepine - anti-epileptic -(Phenobarbitone) -(Phenytoin) -St John's wort (hypericin) -used as anti-depressant **Induction takes hours/days as need to make stuff and mRNA etc.

Platelet activation in thrombosis

•Thrombin - binds to protease-activated receptor (PAR) on platelet surface. •PAR activation --> rise in intracellular Ca2+ in platelet and causes change in shape. •Ca2+ rise --> exocytosis of adenosine diphosphate (ADP) from dense granules 1.ADP receptors •ADP activates P2Y12 receptors --> platelet activation/ aggregation. autocrine and paracrine effects (acts on P2Y12 on own cell and also other cells). 2.Cyclo-oxygenase •PAR activation --> liberates arachidonic acid (AA) •Cyclo-oxygenase (COX) generates thromboxane A2 (TXA2) from AA 3.Glycoprotein IIb/IIIa receptor (GPIIb/IIIa) •TXA2 activation --> expression of GPIIb/IIIa integrin receptor on platelet surface •GPIIb/IIIa - involved in platelet aggregation

Cholinomimetics at high doses can what....

•Two main classes of cholinomimetics - direct (agonists) and indirect (inhibitors of cholinesterase enzymes) •Clinically relevant cholinomimetics act at muscarinic receptors •Cholinomimetics decrease heart rate and cardiac output, increase exocrine gland activity, increase non-vascular smooth muscle contractility and cause miosis •High doses of cholinomimetics not only activate the parasympathetic nervous system, but can activate all autonomic ganglia and ultimately cause depolarising blockade of nAChRs

Anti-platelet actions of Aspirin due to...

•Very high degree of COX-1 inhibition which effectively suppresses TxA2 production by platelets •Covalent binding which permanently inhibits platelet COX-1 •Relatively low capacity to inhibit COX-2 •need LOW dose to allow endothelial resynthesis of COX-2 § Reduces platelet aggregation: 1) Platelets: § Reduces TXA2 production via COX1, no re-production as the platelet has no nucleus. 2) Endothelial cells: § Reduces PGI2 (prostacyclin) synthesis by COX1/2. Reproduction possible due to nucleus and so can replenish prostacyclin. thus prostacyclin reduced but not complete blockade. get higher ratio of prostacyclin to thromboxane. o Thus, less TXA2 and still PGI2 so reduced platelet aggregation.

Reversible anticholinesterase drugs

•e.g. alkaloids: Physostigmine, neostigmine •Compete with acetylcholine for active site on the cholinesterase enzyme •Donate a carbamyl group to the enzyme, blocking the active site and preventing acetylcholine from binding - Carbamyl group removed by slow hydrolysis (mins rather than msecs) - Increase duration of acetylcholine activity in the synapse

NSAIDs and asthmatics

•~10% asthma patients experience worsening symptoms with NSAIDS •Cyclooxygenase inhibition favours production of leukotrienes - bronchoconstrictors •Mouse Knockouts for mPGE2 synthase get aspirin-induced "asthma" , suggesting PGE2 is normally protective •NSAIDS should not be taken by asthmatic patients